ES2299033T3 - DERIVATIVES OF INDOL-2-ONA FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEMS, GASTROINTESTINAL DISORDERS AND CARDIOVASCULAR DISORDERS. - Google Patents
DERIVATIVES OF INDOL-2-ONA FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEMS, GASTROINTESTINAL DISORDERS AND CARDIOVASCULAR DISORDERS. Download PDFInfo
- Publication number
- ES2299033T3 ES2299033T3 ES05745439T ES05745439T ES2299033T3 ES 2299033 T3 ES2299033 T3 ES 2299033T3 ES 05745439 T ES05745439 T ES 05745439T ES 05745439 T ES05745439 T ES 05745439T ES 2299033 T3 ES2299033 T3 ES 2299033T3
- Authority
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- Spain
- Prior art keywords
- dihydro
- indole
- ethyl
- general formula
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 150000003891 oxalate salts Chemical class 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
Derivados de indol-2-ona 3,3-disustituidos de la fórmula general (I): (Ver fórmula) en la que: R 1 y R 2 representan independientemente hidrógeno, halógeno, alquilo con 1 a 7 átomo(s) de carbono o sulfamoilo, R 3 representa hidrógeno o alquilo de cadena lineal o ramificada con 1 a 7 átomo(s) de carbono, R 4 se refiere a alquilo con 1 a 7 átomo(s) de carbono, R 5 es hidrógeno y R 6 indica fenilo que opcionalmente presenta 1 a 3 sustituyente(s) seleccionado(s) de entre halógeno y alquilo con 1 a 7 átomo(s) de carbono que presentan 1 a 3 sustituyente(s) halógeno, o R 5 y R 6 forman, conjuntamente con los átomos de carbono contiguos del anillo tetrahidropiridina, un grupo fenilo o un anillo heterocíclico de 5 ó 6 elementos que contiene un átomo de azufre como heteroátomo, que opcionalmente puede presentar un sustituyente halógeno, m es 1, 2, 3, 4, 5 ó 6, y sales de adición de ácido farmacéuticamente aceptables de los mismos.Indole-2-one 3,3-disubstituted derivatives of the general formula (I): (See formula) in which: R 1 and R 2 independently represent hydrogen, halogen, alkyl with 1 to 7 carbon atom (s) or sulfamoyl, R 3 represents hydrogen or straight or branched chain alkyl with 1 to 7 carbon atom (s), R 4 refers to alkyl with 1 to 7 carbon atom (s), R 5 is hydrogen and R 6 indicates phenyl which optionally has 1 to 3 substituent (s) selected from halogen and alkyl with 1 to 7 carbon atom (s) having 1 to 3 halogen substituent (s), or R 5 and R 6 together form with the contiguous carbon atoms of the tetrahydropyridine ring, a phenyl group or a 5- or 6-element heterocyclic ring containing a sulfur atom as a heteroatom, which may optionally have a halogen substituent, m is 1, 2, 3, 4, 5 or 6, and pharmaceutically acceptable acid addition salts thereof.
Description
Derivados de indol-2-ona para el tratamiento de trastornos del sistema nervioso central, trastornos gastrointestinales y trastornos cardiovasculares.Derivatives indole-2-one for the treatment of central nervous system disorders, disorders gastrointestinal and cardiovascular disorders.
La presente invención se refiere a nuevos derivados de indol-2-ona 3,3-disustituidos, a un procedimiento de preparación de los mismos, a composiciones farmacéuticas que contienen dichos nuevos derivados de indol-2-ona y a la utilización de dichos compuestos en la preparación de un medicamento destinado al tratamiento de enfermedades.The present invention relates to new indole-2-one derivatives 3,3-disubstituted, to a procedure of preparation thereof, to pharmaceutical compositions that contain these new derivatives of indole-2-one and the use of said compounds in the preparation of a medicament intended for Disease treatment
Más particularmente, la presente invención se refiere a nuevos derivados de indol-2-ona 3,3-disustituidos de la fórmula general (I):More particularly, the present invention is refers to new derivatives of indole-2-one 3,3-disubstituted of the general formula (I):
en la que:in the that:
R^{1} y R^{2} son independientemente hidrógeno, halógeno, alquilo con 1 a 7 átomos de carbono o sulfamoilo,R1 and R2 are independently hydrogen, halogen, alkyl with 1 to 7 carbon atoms or sulfamoyl,
R^{3} es hidrógeno o alquilo de cadena lineal o ramificada con 1 a 7 átomos de carbono,R 3 is hydrogen or straight chain alkyl or branched with 1 to 7 carbon atoms,
R^{4} es alquilo con 1 a 7 átomos de carbono,R 4 is alkyl with 1 to 7 atoms of carbon,
R^{5} es hidrógeno y R^{6} indica fenilo que opcionalmente presenta 1 a 3 sustituyentes seleccionados de entre halógeno y alquilo con 1 a 7 átomos de carbono que presenta 1 a 3 sustituyentes halógeno, oR 5 is hydrogen and R 6 indicates phenyl that optionally presents 1 to 3 substituents selected from halogen and alkyl with 1 to 7 carbon atoms having 1 to 3 halogen substituents, or
R^{5} y R^{6} forman, conjuntamente con los átomos de carbono contiguos del anillo tetrahidropiridina, fenilo o un anillo hterocíclico de 5 ó 6 elementos que contiene un azufre como heteroátomo, que opcionalmente puede presentar un sustituyente halógeno,R 5 and R 6 form, together with the contiguous carbon atoms of the tetrahydropyridine, phenyl or a 5 or 6 element heterocyclic ring containing a sulfur as a heteroatom, which may optionally have a substituent halogen,
m es 1, 2, 3, 4, 5 ó 6,m is 1, 2, 3, 4, 5 or 6,
y sales de adición de ácido farmacéuticamente aceptables de los mismos.and acid addition salts pharmaceutically acceptable of the same.
La patente US nº 4.452.808 da a conocer derivados de 4-aminoalquil-indol-2-ona que presentan una actividad selectiva de receptor D_{2}. Estos compuestos pueden utilizarse para el tratamiento de la hipertensión. Uno de los compuestos proporcionados por la presente patente, denominado 4-[2-(di-N-propilamino)etil]-2(3H)-indolona, se utiliza en el tratamiento clínico.US Patent No. 4,452,808 discloses derivatives of 4-aminoalkyl-indole-2-one which exhibit a selective activity of D2 receptor. These Compounds can be used for the treatment of hypertension. One of the compounds provided by the present patent, called 4- [2- (di-N-propylamino) ethyl] -2 (3H) -indolone, It is used in clinical treatment.
La patente europea nº 281.309 proporciona derivados de indol-2-ona que presentan un sustituyente arilpiperazinil-alquilo en la posición 5, que pueden aplicarse para el tratamiento de las condiciones psicóticas. Uno de los compuestos descritos en la presente patente, denominado 5-[2-[4-(1,2-benzisotiazol-3-il)-1-piperazinil]-etil]-6-cloro-1,3-dihidro-2H-indol-2-ona, ejerce su actividad mediante la interacción con receptores de D_{2}, 5-HT_{1A} y 5-HT_{2} y se utiliza en el tratamiento clínico.European Patent No. 281,309 provides indole-2-one derivatives that they have an arylpiperazinyl alkyl substituent in position 5, which can be applied for the treatment of psychotic conditions One of the compounds described in the This patent, called 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one, exerts its activity through interaction with recipients of D2, 5-HT1A and 5-HT2 and It is used in clinical treatment.
La patente europea nº 376.607 da a conocer derivados de indol-2-ona sustituidos en la posición 3 con un grupo alquilpiperazinilo, que ejercen su actividad sobre receptores 5-HT_{1A} y resultan útiles para el tratamiento de trastornos del sistema nervioso central.European Patent No. 376,607 discloses substituted indole-2-one derivatives in position 3 with an alkylpiperazinyl group, which exert their activity on 5-HT1A receptors and result useful for the treatment of nervous system disorders central.
En la solicitud de patente internacional WO 98/008816, se dan a conocer derivados de indol-2-ona que contienen un alquilpiperazinilo sustituido, un alquil-piperidinilo sustituido o un grupo alquil-ciclohexilo en la posición 3. Estos compuestos ejercen una actividad antipsicótica.In the international patent application WO 98/008816, derivatives of indole-2-one containing a substituted alkylpiperazinyl, a substituted alkyl-piperidinyl or a group alkyl-cyclohexyl at position 3. These Compounds exert an antipsychotic activity.
La aceleración del desarrollo técnico-social en el siglo XX ha constituido una obsesión permanente de adaptación para el ser humano, que en casos adversos, puede conducir a la aparición de trastornos de adaptación. Los trastornos de adaptación constituyen un importante factor de riesgo en el desarrollo de enfermedades de origen mental o psicosomático, tal como el síndrome de ansiedad, el trastorno de estrés, la depresión, la esquizofrenia, los trastornos de los órganos de los sentidos, las enfermedades gastrointestinales, las enfermedades cardiovasculares o los trastornos renales.Acceleration of development technical-social in the twentieth century has constituted a permanent obsession of adaptation for the human being, that in cases Adverse, may lead to the appearance of adaptive disorders. Adaptation disorders are an important factor of risk in the development of diseases of mental origin or psychosomatic, such as anxiety syndrome, disorder stress, depression, schizophrenia, disorders of sense organs, gastrointestinal diseases, cardiovascular diseases or kidney disorders.
Para el tratamiento de los patrones clínicos indicados anteriormente, se han aplicado la mayoría de fármacos más extendidos que ejercen su actividad sobre el sistema benzodiazepina (por ejemplo el diazepam) o sobre receptores 5-HT_{1A} centrales (por ejemplo buspirón, ziprasidón).For the treatment of clinical patterns indicated above, most other drugs have been applied extended that exert their activity on the benzodiazepine system (for example diazepam) or on receptors Central 5-HT_ {1A} (for example, buspirón, ziprasidon).
Los fármacos que actúan sobre los receptores 5-HT_{1A} que se han aplicado hasta el momento en la terapia se ven acompañados, sin embargo, por varias desventajas y efectos secundarios no deseados. Es una desventaja que el efecto ansiolítico pueda conseguirse sólo tras un tratamiento que dura por lo menos 10 a 14 días. Además, tras la administración inicial, se produce un efecto anxiogénico. Respecto a los efectos secundarios, con frecuencia se ha observado clinomanía, somnolencia, vértigo, alucinaciones, cefalea, perturbaciones cognitivas o náuseas.The drugs that act on the receptors 5-HT_ {1A} that have been applied so far in Therapy is accompanied, however, by several disadvantages and unwanted side effects. It is a disadvantage that the effect anxiolytic can be achieved only after a treatment that lasts for At least 10 to 14 days. In addition, after the initial administration, It produces an anxiogenic effect. Regarding the side effects, clinomania, drowsiness, dizziness have often been observed hallucinations, headache, cognitive disturbances or nausea.
El objetivo de la presente invención es desarrollar ingredientes farmacéuticos que carezcan de las desventajas anteriormente especificadas y de los efectos secundarios no deseados característicos de los agentes activos que se unen a los receptores 5-HT_{1A} y que, simultáneamente, pueden utilizarse para el tratamiento de trastornos del sistema nervioso central.The objective of the present invention is develop pharmaceutical ingredients that lack the disadvantages specified above and the effects unwanted side effects characteristic of active agents that bind to the 5-HT1A receptors and that, simultaneously, they can be used for the treatment of central nervous system disorders.
La invención se basa en el reconocimiento de que los derivados 3,3-dialquil-sustituidos de indol-2-ona de fórmula general (I) presentan un efecto ansiolítico significativo aunque, inesperadamente en contraste con los compuestos de la técnica anterior de estructura similar, no se unen a los receptores 5-HT_{1A}. En consecuencia, los compuestos según la invención carecen de los efectos secundarios característicos de los compuestos que se unen a dicho receptor.The invention is based on the recognition that derivatives 3,3-dialkyl-substituted indole-2-one of general formula (I) they have a significant anxiolytic effect although, unexpectedly in contrast to the compounds of the art previous of similar structure, do not bind to receptors 5-HT_ {1A}. Consequently, the compounds according to the invention lack the characteristic side effects of the compounds that bind to said receptor.
Según un aspecto de la presente invención se proporcionan nuevos derivados de indol-2-ona 3,3-disustituidos de fórmula general (I), en los que:According to one aspect of the present invention, provide new derivatives of indole-2-one 3,3-disubstituted of general formula (I), in the that:
R^{1} y R^{2} representan hidrógeno, halógeno, alquilo con 1 a 7 átomos de carbono o sulfamoilo,R1 and R2 represent hydrogen, halogen, alkyl with 1 to 7 carbon atoms or sulfamoyl,
R^{3} representa hidrógeno o alquilo de cadena lineal o ramificada con 1 a 7 átomos de carbono,R 3 represents hydrogen or chain alkyl linear or branched with 1 to 7 carbon atoms,
R^{4} indica alquilo con 1 a 7 átomos de carbono,R 4 indicates alkyl with 1 to 7 atoms of carbon,
R^{5} es hidrógeno y R^{6} se refiere a fenilo que opcionalmente presenta 1 a 3 sustituyentes seleccionados de entre halógeno y alquilo con 1 a 7 átomos de carbono que presentan 1 a 3 sustituyentes halógeno, oR 5 is hydrogen and R 6 refers to phenyl that optionally has 1 to 3 substituents selected between halogen and alkyl with 1 to 7 carbon atoms that have 1 to 3 halogen substituents, or
R^{5} y R^{6} forman, conjuntamente con los átomos de carbono contiguos del anillo tetrahidropiridina, un grupo fenilo o un anillo heterocíclico de 5 ó 6 elementos que contiene un azufre como heteroátomo, que puede presentar opcionalmente un sustituyente halógeno,R 5 and R 6 form, together with the contiguous carbon atoms of the tetrahydropyridine ring, a group phenyl or a 5 or 6 element heterocyclic ring containing a sulfur as a heteroatom, which can optionally present a halogen substituent,
m es 1, 2, 3, 4, 5 ó 6,m is 1, 2, 3, 4, 5 or 6,
y sales de adición de ácido farmacéuticamente aceptables de los mismos.and acid addition salts pharmaceutically acceptable of the same.
El término "alquilo" utilizado en la presente memoria pretende referirse a grupos hidrocarburo saturados de cadena lineal o ramificada con 1 a 7, preferentemente 1 a 4 átomos de carbono (por ejemplo metilo, etilo, 1-propilo, 2-propilo, n-butilo, isobutilo o terc-butilo, etc.).The term "alkyl" used in the This report is intended to refer to saturated hydrocarbon groups straight or branched chain with 1 to 7, preferably 1 to 4 carbon atoms (for example methyl, ethyl, 1-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc.).
El término "halógeno" comprende los átomos de flúor, cloro, bromo y yodo y preferentemente es cloro o bromo.The term "halogen" comprises atoms of fluorine, chlorine, bromine and iodine and preferably it is chlorine or bromine.
El grupo saliente puede ser un grupo alquilsulfoniloxi o arilsulfoniloxi, por ejemplo metilsulfoniloxi o p-toluenosulfoniloxi, o un átomo de halógeno, preferentemente bromo o cloro.The outgoing group can be a group alkylsulfonyloxy or arylsulfonyloxy, for example methylsulfonyloxy or p-toluenesulfonyloxy, or a halogen atom, preferably bromine or chlorine.
La expresión "sales de adición de ácido farmacéuticamente aceptables" se refiere a sales no tóxicas de los compuestos de fórmula general (I) formadas con ácidos orgánicos o inorgánicos farmacéuticamente aceptables. Los ácidos inorgánicos adecuados para la formación de sales son, por ejemplo, ácido clorhídrico, ácido bromhídrico, ácido fosfórico, ácido sulfúrico o ácido nítrico. Como ácidos orgánicos pueden utilizarse los ácidos fórmico, acético, propiónico, maleico, fumárico, succínico, láctico, málico, tartárico, cítrico, ascórbico, malónico, oxálico, mandélico, glicólico, ftálico, bencensulfónico, p-toluen-sulfónico, naftálico o metansulfónico. Además, los carbonatos e hidrocarbonatos también se consideran sales farmacéuticamente aceptables.The expression "acid addition salts pharmaceutically acceptable "refers to non-toxic salts of the compounds of general formula (I) formed with organic acids or pharmaceutically acceptable inorganic. Inorganic acids suitable for salt formation are, for example, acid hydrochloric, hydrobromic acid, phosphoric acid, sulfuric acid or nitric acid. As organic acids acids can be used formic, acetic, propionic, maleic, fumaric, succinic, lactic, malic, tartaric, citric, ascorbic, malonic, oxalic, Mandelic, glycolic, phthalic, benzenesulfonic, p-toluene-sulfonic, naphthalic or methanesulfonic acid In addition, carbonates and hydrocarbonates are also they consider pharmaceutically acceptable salts.
A un subgrupo de los compuestos de fórmula general (I) que presentan propiedades farmacéuticas valiosas pertenecen los compuestos en los que R^{1} y R^{2} representan independientemente hidrógeno, alquilo de cadena lineal o ramificada que presenta 1 a 7 átomos de carbono o halógeno, R^{3} es hidrógeno o un alquilo de cadena lineal o ramificada con 1 a 7 átomos de carbono, R^{4} representa alquilo de cadena lineal o ramificada con 1 a 4 átomos de carbono, R^{5} indica hidrógeno y R^{6} se refiere a fenilo que opcionalmente presenta un halógeno o un sustituyente trifluorometilo, o R^{5} y R^{6} forman, conjuntamente con los átomos de carbono contiguos del anillo tetrahidropiridina, un anillo heterocíclico de 5 ó 6 elementos que contiene un átomo de azufre como heteroátomo y que opcionalmente presenta un átomo de halógeno, preferentemente cloro, m es 3, 4 ó 5, y sales de adición de ácido farmacéuticamente aceptables de los mismos.To a subset of the compounds of formula general (I) that present valuable pharmaceutical properties the compounds in which R 1 and R 2 represent independently hydrogen, straight or branched chain alkyl having 1 to 7 carbon or halogen atoms, R 3 is hydrogen or a straight or branched chain alkyl with 1 to 7 carbon atoms, R 4 represents straight chain alkyl or branched with 1 to 4 carbon atoms, R 5 indicates hydrogen and R 6 refers to phenyl which optionally has a halogen or a trifluoromethyl substituent, or R 5 and R 6 form, together with the contiguous carbon atoms of the ring tetrahydropyridine, a heterocyclic ring of 5 or 6 elements that it contains a sulfur atom as a heteroatom and that optionally it has a halogen atom, preferably chlorine, m is 3, 4 or 5, and pharmaceutically acceptable acid addition salts of the same.
A un subgrupo de los compuestos de fórmula general (I) que presentan una actividad particularmente preferida pertenecen los derivados en los que R^{1}, R^{2} y R^{3} representan independientemente hidrógeno o halógeno, R^{4} es etilo, R^{5} y R^{6} forman, conjuntamente con los átomos de carbono contiguos del anillo dihidropiridina, un anillo heterocíclico de 5 elementos que contiene azufre como heteroátomo, que opcionalmente presenta un halógeno, m es 5, y sales de adición de ácido farmacéuticamente aceptables de los mismos.To a subset of the compounds of formula general (I) presenting a particularly preferred activity Derivatives in which R 1, R 2 and R 3 belong independently represent hydrogen or halogen, R 4 is ethyl, R 5 and R 6 form, together with the atoms of contiguous carbon of the dihydropyridine ring, a ring 5-element heterocyclic containing sulfur as a heteroatom, which optionally has a halogen, m is 5, and addition salts of pharmaceutically acceptable acid thereof.
A otro subgrupo de los compuestos de fórmula general (I) que presentan una actividad particularmente preferida pertenecen los derivados en los que:To another subgroup of the compounds of formula general (I) presenting a particularly preferred activity Derivatives in which:
R^{1}, R^{2} y R^{3} representan independientemente hidrógeno o halógeno, R^{4} es etilo, R^{5} representa hidrógeno, R^{6} es fenilo que presenta un sustituyente halógeno, preferentemente flúor, m es 4, y sales de adición de ácido farmacéuticamente aceptables de los mismos.R 1, R 2 and R 3 represent independently hydrogen or halogen, R 4 is ethyl, R 5 represents hydrogen, R 6 is phenyl having a substituent halogen, preferably fluorine, m is 4, and addition salts of pharmaceutically acceptable acid thereof.
Según un aspecto adicional de la presente invención, se proporciona un procedimiento para la preparación de los compuestos de fórmula general (I) y sales de adición de ácido farmacéuticamente aceptables de los mismos, que comprende:According to an additional aspect of the present invention, a process for the preparation of the compounds of general formula (I) and acid addition salts Pharmaceutically acceptable thereof, comprising:
(a) hacer reaccionar un compuesto de fórmula general (II),(a) react a compound of formula general (II),
en la que R^{1}-R^{4} son tal como se ha indicado anteriormente y L es un grupo saliente, preferentemente cloro o bromo, m es 1, 2, 3, 4, 5 ó 6, con un derivado piridina de fórmula general (III),in which R 1 -R 4 are as indicated above and L is a leaving group, preferably chlorine or bromine, m is 1, 2, 3, 4, 5 or 6, with a pyridine derivative of the formula general (III),
en la que R^{5} y R^{6} son tal como se ha indicado anteriormente, owherein R 5 and R 6 are such as indicated above, or
(b) hacer reaccionar un compuesto de fórmula general (IV),(b) react a compound of formula general (IV),
en la que R^{1}, R^{2}, R^{3} y R^{4} son tal como se ha indicado anteriormente, con un compuesto de fórmula general (V),in which R 1, R 2, R 3 and R 4 are as indicated above, with a compound of general formula (V),
(V)L-(CH_{2})_{m}-L'(V) L- (CH2) m -L '
en la que m es 1, 2, 3, 4, 5 ó 6, L y L' representan un grupo saliente, preferentemente cloro o bromo, en presencia de una base fuerte, opcionalmente halogenado el compuesto de fórmula general (II) obtenido de eta manera, en la que R^{2} es hidrógeno, y haciendo reaccionar el compuesto de fórmula general (II) obtenido de esta manera, en la que L es un grupo saliente, preferentemente cloro o bromo, R^{2} es hidrógeno o halógeno y m es 1, 2, 3, 4, 5 ó 6, con un derivado piridina de fórmula general (III), en la que R^{5} y R^{6} son tal como se ha indicado anteriormente, en presencia de un agente de unión a los ácidos, owhere m is 1, 2, 3, 4, 5 or 6, L and L 'represent a leaving group, preferably chlorine or bromine, in the presence of a strong base, optionally halogenated the compound of general formula (II) obtained in this manner, in which R2 is hydrogen, and reacting the compound of formula general (II) obtained in this way, in which L is a group outgoing, preferably chlorine or bromine, R2 is hydrogen or halogen and m is 1, 2, 3, 4, 5 or 6, with a pyridine derivative of general formula (III), in which R 5 and R 6 are as indicated above, in the presence of a binding agent to acids, or
(c) hacer reaccionar un compuesto de fórmula general (IV), en la que R^{1}, R^{2}, R^{3} y R^{4} son tal como se ha indicado anteriormente, con un derivado piridina de fórmula general (VI),(c) reacting a compound of formula general (IV), in which R1, R2, R3 and R4 are such as indicated above, with a pyridine derivative of general formula (VI),
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en la que L es sulfoniloxi o halógeno, preferentemente cloro o bromo; R^{5} y R^{6} son tal como se ha indicado anteriormente; m es 1, 2, 3, 4, 5 ó 6, en presencia de una base fuerte, y opcionalmente halogenando el producto obtenido de esta manera, en el que R^{2} es hidrógeno, o liberando la base libre de una sal del mismo o convirtiéndolo en una sal de adición de ácido orgánico o inorgánico farmacéuticamente aceptable del mismo.in which L is sulfonyloxy or halogen, preferably chlorine or bromine; R 5 and R 6 are such as indicated above; m is 1, 2, 3, 4, 5 or 6, in presence of a strong base, and optionally halogenating the product obtained in this way, in which R2 is hydrogen, or releasing the free base of a salt thereof or turning it into a pharmaceutically organic or inorganic acid addition salt acceptable from same.
Los compuestos de fórmulas generales (III), (V) y (VI) son conocidos en la literatura y pueden prepararse mediante procedimientos análogos.Compounds of general formulas (III), (V) and (VI) are known in the literature and can be prepared by analogous procedures
Cuando se aplica cualquiera de las variantes de procedimiento anteriormente indicadas, los sustituyentes deseados pueden introducirse o convertirse según los procedimientos conocidos de la literatura durante cualquiera de las etapas de reacción. Si se desea, siguiendo la aplicación de cualquier variante de procedimiento, la base libre correspondiente del producto de fórmula general (I) puede liberarse de su sal o convertirse en una sal de adición de ácido farmacéuticamente aceptable del mismo.When any of the variants of procedure indicated above, the desired substituents can be introduced or converted according to known procedures of the literature during any of the reaction stages. Yes desired, following the application of any variant of procedure, the corresponding free base of the product of general formula (I) can be released from its salt or become a pharmaceutically acceptable acid addition salt thereof.
Según la variante (a), el compuesto de fórmula general (I) pueden prepararse haciendo reaccionar un compuesto de fórmula general (II), en el que R^{1}-R^{4} y M son tal como se indica anteriormente y L es un grupo saliente, preferentemente bromo o cloro, con un compuesto de fórmula general (III), en el que R^{5} y R^{6} son tal como se ha indicado anteriormente, según los procedimientos conocidos de la literatura [Houben-Weyl: Methoden de organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, 4ª edición, vol. E16d (editor: D. Klamann); R.C. Larock: Comprehensive Organic Transformations, 2ª edición, John Wiley & Sons, New York, 1999, 789; D.A. Walsh, Y-H. Chen, J.B. Green, J.C. Nolan, J.M. Yanni, J. Med. Chem. 33:1823-1827, 1990].According to variant (a), the compound of formula general (I) can be prepared by reacting a compound of general formula (II), wherein R 1 -R 4 and M they are as indicated above and L is a leaving group, preferably bromine or chlorine, with a compound of general formula (III), in which R 5 and R 6 are as indicated previously, according to the known procedures of the literature [Houben-Weyl: Methoden of organischen Chemie, Georg Thieme Verlag, Stuttgart, 1992, 4th edition, vol. E16d (editor: D. Klamann); R.C. Larock: Comprehensive Organic Transformations, 2nd edition, John Wiley & Sons, New York, 1999, 789; GIVES. Walsh, Y-H Chen, J.B. Green, J.C. Nolan, J.M. Yanni, J. Med. Chem. 33: 1823-1827, 1990].
Durante la preparación de los compuestos de fórmula general (II), puede llevarse a cabo la formación de los sustituyentes en sucesión opcional según los procedimientos conocidos de la literatura. Los compuestos de fórmula general (II) preferentemente se preparan haciendo reaccionar un compuesto de fórmula general (V), en el que L y m son tal como se ha indicado anteriormente y L' es un grupo saliente o un grupo que puede convertirse en un grupo saliente, con un compuesto de fórmula general (IV), en el que R^{1}-R^{4} son tal como se ha indicado anteriormente [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4a edición, vol. V/2b; A.R. Katritzky, Ch.W. Rees: Comprehensive Heterocyclic Chemistry, primera edición, Pergamon, Oxford, 1984, vol. 4 (editor: C.W. Bird, G.W.H. Cheeseman), 98-150 y 339-366; G.M. Karp, Org. Prep. Proc. Int. 25:481-513, 1993; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597].During the preparation of the compounds of general formula (II), the formation of the optional succession substituents according to the procedures known from the literature. The compounds of general formula (II) preferably they are prepared by reacting a compound of general formula (V), in which L and m are as indicated above and L 'is an outgoing group or a group that can become a leaving group, with a compound of formula general (IV), in which R 1 -R 4 they are as indicated above [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4th edition, vol. V / 2b; A.R. Katritzky, Ch.W. Rees: Comprehensive Heterocyclic Chemistry, first edition, Pergamon, Oxford, 1984, vol. 4 (editor: C.W. Bird, G.W.H. Cheeseman), 98-150 and 339-366; G.M. Karp, Org. Prep. Proc. Int. 25: 481-513, 1993; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597].
Los compuestos de fórmula general (I) también pueden prepararse según la variante (c) de procedimiento haciendo reaccionar un compuesto de fórmula general (IV), en la que R^{1}-R^{4} son tal como se ha indicado anteriormente, con un compuesto de fórmula general (VI), en la que R^{5}, R^{6} y m son tal como se ha indicado anteriormente y L es un grupo saliente, según los procedimientos conocidos de la literatura [R.J. Sundberg: The chemistry of indoles, Academic Press, New York, 1970, capítulo VII; G.M. Karp Org, Prep. Proc. Int. 25:481-513, 1993; A.S. Kende, J.C. Hodges Synth. Commun. 12:1-10, 1982; W.W. Wilkerson, A.A. Kergaye, S. W. Tam. J. Med. Chem. 36:2899-2907, 1993].The compounds of general formula (I) also can be prepared according to the procedure variant (c) by reacting a compound of general formula (IV), in which R 1 -R 4 are as indicated above, with a compound of general formula (VI), in which R 5, R 6 and m are as indicated above and L it is a leaving group, according to the known procedures of the literature [R.J. Sundberg: The chemistry of indoles, Academic Press, New York, 1970, chapter VII; G.M. Karp Org, Prep. Proc. Int. 25: 481-513, 1993; ACE. Kende, J.C. Hodges Synth. Commun. 12: 1-10, 1982; W.W. Wilkerson, A.A. Kergaye, S. W. Tam. J. Med. Chem. 36: 2899-2907, 1993].
Durante la preparación de los compuestos de fórmula general (I), también puede llevarse a cabo la formación de los sustituyentes R^{1}-R^{6} en diferentes sucesiones en la última etapa de reacción. En este caso, se utiliza como material de partida un compuesto de fórmula general (I) que contiene hidrógeno en lugar del sustituyente que debe formarse. La introducción y conversión de los sustituyentes puede llevarse a cabo siguiendo los procedimientos conocidos de la literatura [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4a edición, IV/1a-d; vol. V/2b]. Durante la introducción de los sustituyentes, puede resultar necesaria la aplicación o eliminación de grupos protectores. Dichos procedimientos se especifican en T.W. Greene, Protective Groups in organic synthesis, John Wiley & Sons, 1981.During the preparation of the compounds of general formula (I), the formation of the R 1 -R 6 substituents in different successions in the last reaction stage. In this case, it is used as a starting material a compound of general formula (I) that It contains hydrogen instead of the substituent to be formed. The Introduction and conversion of substituents can be carried out following the known procedures of the literature [Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart, 1977, 4th edition, IV / 1a-d; vol. V / 2b]. During the introduction of substituents, application or removal may be necessary of protective groups. These procedures are specified in T.W. Greene, Protective Groups in organic synthesis, John Wiley & Sons, 1981.
El compuesto de fórmula general (IV), en la que R^{1}-R^{4} son tal como se ha indicado anteriormente, se pueden preparar aplicando procedimientos conocidos, llevándose a cabo la formación de los sustituyentes en una sucesión opcional, según los procedimientos conocidos de la literatura [A. R. Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1ª Edition, Pergamon, Oxford, 1984, vol. 4 (ed.: C. W. Bird, G. W. H. Cheeseman), 98-150 y 339-366; C. Gautier, M. Aletru, Ph. Bovy WO 99/62900; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597; G. M. Karp Org. Prep. Proc. Int. 1993, 25, 481-513; A. S. Kende, J. C. Hodges Synth. Commun. 1982, 12, 1-10].The compound of general formula (IV), in which R 1 -R 4 are as indicated previously, they can be prepared by applying procedures known, carrying out the formation of substituents in an optional sequence, according to the known procedures of the literature [A. R. Katritzky, Ch. W. Rees: Comprehensive Heterocyclic Chemistry, 1st Edition, Pergamon, Oxford, 1984, vol. 4 (ed .: C. W. Bird, G. W. H. Cheeseman), 98-150 and 339-366; C. Gautier, M. Aletru, Ph. Bovy WO 99/62900; B. Volk, T. Mezei, Gy. Simig Synthesis 2002, 595-597; G. M. Karp Org. Prep. Proc. Int. 1993, 25, 481-513; A. S. Kende, J. C. Hodges Synth. Commun. 1982, 12, 1-10].
Los compuestos de fórmula general (I) preparados mediante los procedimientos según la invención pueden liberarse de las sales de los mismos o convertirse en sales de adición de ácido farmacéuticamente aceptables según los procedimientos conocidos de la literatura.The compounds of general formula (I) prepared by the methods according to the invention they can be released from the salts thereof or become acid addition salts pharmaceutically acceptable according to the known procedures of Literature.
Según un aspecto adicional de la presente invención se proporcionan composiciones farmacéuticas que comprenden como ingrediente activo un compuesto de fórmula general (I) o una sal de adición de ácido farmacéuticamente aceptable del mismo en mezcla con uno o más portadores o agentes auxiliares convencionales.According to an additional aspect of the present invention pharmaceutical compositions are provided comprising as active ingredient a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof in mixing with one or more carriers or auxiliary agents conventional.
Las composiciones farmacéuticas según la presente invención contienen generalmente 0,1 a 95% en peso, preferentemente 1 a 50% en peso, particularmente 5 a 30% en peso del ingrediente activo.The pharmaceutical compositions according to the present invention generally contain 0.1 to 95% by weight, preferably 1 to 50% by weight, particularly 5 to 30% by weight of the active ingredient.
Las composiciones farmacéuticas de la presente invención pueden resultar adecuadas para la administración oral (por ejemplo polvos, tabletas, tabletas recubiertas, cápsulas, microcápsulas, píldoras, soluciones, suspensiones o emulsiones), parenteral (por ejemplo soluciones de inyección para utilización intravenosa, intramuscular, subcutánea o intraperitoneal), rectal (por ejemplo supositorios), transdérmica (por ejemplo parches) o local (por ejemplo pomadas o parches) o para la aplicación en forma de implantes. Las composiciones farmacéuticas sólidas, blandas o líquidas según la invención se pueden preparar mediante procedimientos aplicados convencionalmente en la industria farmacéutica.The pharmaceutical compositions herein invention may be suitable for oral administration (e.g. powders, tablets, coated tablets, capsules, microcapsules, pills, solutions, suspensions or emulsions), parenteral (for example injection solutions for use intravenous, intramuscular, subcutaneous or intraperitoneal), rectal (for example suppositories), transdermal (for example patches) or local (for example ointments or patches) or for application in form of implants Solid, soft or pharmaceutical compositions Liquids according to the invention can be prepared by conventionally applied procedures in the industry Pharmaceutical
Las composiciones farmacéuticas sólidas para la administración oral que contienen los compuestos de fórmula general (I) o sales de adición de ácido farmacéuticamente aceptables de los mismos pueden comprender rellenos o portadores (tales como lactosa, glucosa, almidón, fosfato de potasio, celulosa microcristalina), agentes ligantes (tales como gelatina, sorbitol, polivinilpirrolidona), desintegrantes (tales como croscarmelosa, carboximetilcelulosa sódica, crospovidona), agentes auxiliares de tableteo (tales como estearato de magnesio, talco, polietilenglicol, ácido silícico, dióxido de silicio) y agentes activos en superficie (por ejemplo laurilsulfato sódico).Solid pharmaceutical compositions for oral administration containing the compounds of the general formula (I) or pharmaceutically acceptable acid addition salts of the they may comprise fillers or carriers (such as lactose, glucose, starch, potassium phosphate, microcrystalline cellulose), binding agents (such as gelatin, sorbitol, polyvinylpyrrolidone), disintegrants (such as croscarmellose, sodium carboxymethyl cellulose, crospovidone), auxiliary agents tabletting (such as magnesium stearate, talc, polyethylene glycol, silicic acid, silicon dioxide) and agents surface active (for example sodium lauryl sulfate).
Las composiciones líquidas adecuadas para la administración oral pueden ser soluciones, suspensiones o emulsiones. Dichas composiciones pueden contener agentes de suspensión (por ejemplo gelatina, carboximetilcelulosa), emulsionantes (por ejemplo monooleato de sorbitán), solventes (por ejemplo agua, aceites, glicerol, propilenglicol, etanol), agentes tamponadores (por ejemplo tampones acetato, fosfato, citrato) y conservantes (por ejemplo metil-4-hidroxibenzoato, etc.).Liquid compositions suitable for oral administration may be solutions, suspensions or emulsions Such compositions may contain agents of suspension (for example gelatin, carboxymethyl cellulose), emulsifiers (for example sorbitan monooleate), solvents (for example water, oils, glycerol, propylene glycol, ethanol), agents buffers (eg acetate, phosphate, citrate buffers) and preservatives (for example methyl-4-hydroxybenzoate, etc.).
Las composiciones farmacéuticas líquidas adecuadas para la administración parenteral son generalmente soluciones isotónicas estériles que opcionalmente contienen, además del solvente, agentes tamponadores y conservantes.Liquid pharmaceutical compositions suitable for parenteral administration are generally sterile isotonic solutions that optionally contain, in addition of the solvent, buffering agents and preservatives.
Las composiciones farmacéuticas blandas que contienen como ingrediente activo un compuesto de fórmula general (I) o una sal de adición de ácido farmacéuticamente aceptable del mismo, tal como supositorios, contienen el ingrediente activo dispersado homogéneamente en el material básico del supositorio (por ejemplo en polietilenglicol o manteca de cacao).The soft pharmaceutical compositions that contain as an active ingredient a compound of general formula (I) or a pharmaceutically acceptable acid addition salt of the same, as suppositories, contain the active ingredient homogeneously dispersed in the suppository basic material (by example in polyethylene glycol or cocoa butter).
Según un aspecto adicional de la presente invención, se proporciona la utilización de un derivado de indol-2-ona de fórmula general (I) o una sal de adición de ácido farmacéuticamente aceptable del mismo para la preparación de composiciones farmacéuticas adecuadas para el tratamiento o la profilaxis de trastornos del sistema nervioso central o trastornos psicosomáticos, incluyendo síndromes de ansiedad, particularmente trastornos de ansiedad generalizada, trastorno de pánico, trastorno compulsivo, fobia social, agorafobia, fobias relacionadas con situaciones específicas, trastornos de estrés post-traumático, perturbaciones post-traumáticas de la memoria, alteraciones cognitivas, disfunción sexual de origen en el sistema nervioso central, depresión, esquizofrenia, enfermedades gastrointestinales y enfermedades cardiovasculares.According to an additional aspect of the present invention, the use of a derivative of indole-2-one of general formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of pharmaceutical compositions suitable for the treatment or prophylaxis of nervous system disorders central or psychosomatic disorders, including syndromes of anxiety, particularly generalized anxiety disorders, panic disorder, compulsive disorder, social phobia, agoraphobia, phobias related to specific situations, disorders of post-traumatic stress, disturbances post-traumatic memory, alterations Cognitive, sexual dysfunction of origin in the nervous system central depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
Según un aspecto adicional de la presente invención, se proporciona la utilización de un derivado de indol-2-ona de fórmula general (I) o una sal de adición de ácido farmacéuticamente aceptable del mismo para la preparación de composiciones farmacéuticas adecuadas para el tratamiento o profilaxis de trastornos del sistema nervioso central o trastornos psicosomáticos, incluyendo síndromes de ansiedad, particularmente trastornos de ansiedad generalizada, trastorno de pánico, trastorno compulsivo, fobia social, agorafobia, fobias relacionadas con situaciones específicas, trastornos de estrés post-traumático, perturbaciones de la memoria causadas por trauma, alteraciones cognitivas, disfunción sexual de origen en el sistema nervioso central, depresión, esquizofrenia, enfermedades gastrointestinales y enfermedades cardiovasculares.According to an additional aspect of the present invention, the use of a derivative of indole-2-one of general formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of pharmaceutical compositions suitable for the treatment or prophylaxis of nervous system disorders central or psychosomatic disorders, including syndromes of anxiety, particularly generalized anxiety disorders, panic disorder, compulsive disorder, social phobia, agoraphobia, phobias related to specific situations, disorders of post-traumatic stress, memory disturbances caused by trauma, cognitive disorders, sexual dysfunction of origin in the central nervous system, depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
Las composiciones farmacéuticas según la presente invención pueden prepararse mediante procedimientos conocidos de la industria farmacéutica. El ingrediente activo se mezcla con portadores sólidos o líquidos farmacéuticamente aceptables y/o agentes auxiliares y la mezcla se transforma en una forma galénica. Los portadores y agentes auxiliares conjuntamente con los procedimientos que pueden utilizarse en la industria farmacéutica se dan a conocer en la literatura (Remington's Pharmaceutical Sciences, edición 18ª, Mack Publishing Co., Easton, USA, 1990).The pharmaceutical compositions according to the present invention can be prepared by procedures known from the pharmaceutical industry. The active ingredient is mixture with pharmaceutically solid or liquid carriers acceptable and / or auxiliary agents and the mixture is transformed into a Galenic form The carriers and auxiliary agents together with the procedures that can be used in the industry Pharmaceuticals are known in the literature (Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, USA, 1990).
Las composiciones farmacéuticas según la presente invención contienen generalmente una unidad de dosificación. La dosis diaria para el adulto humano puede ser generalmente 0,1 a 1.000 mg/kg de peso corporal de un compuesto de fórmula general (I) o una sal de adición de ácido farmacéuticamente aceptable del mismo. Dicha dosis diaria puede administrarse en una o más partes. La dosis diaria real depende de varios factores y la determina el médico.The pharmaceutical compositions according to the present invention generally contain a unit of dosage. The daily dose for the human adult can be generally 0.1 to 1,000 mg / kg body weight of a compound of general formula (I) or a pharmaceutically acid addition salt acceptable of it. Said daily dose can be administered in a or more parts The actual daily dose depends on several factors and the determines the doctor.
Según un aspecto adicional de la presente invención, se proporciona la utilización de los compuestos de fórmula (I) o sales de adición de ácido farmacéuticamente aceptables de los mismos para el tratamiento o profilaxis de trastornos del sistema nervioso central y de trastornos psicosomáticos, incluyendo síndrome de ansiedad, particularmente trastornos de ansiedad generalizada, trastorno de pánico, trastorno compulsivo, fobia social, agorafobia, fobias relacionadas con situaciones específicas, trastornos de estrés, trastornos post-traumáticos de la memoria, alteraciones cognitivas, disfunción sexual de origen en el sistema nervioso central, depresión, esquizofrenia, enfermedades gastrointestinales y enfermedades cardiovasculares.According to an additional aspect of the present invention, the use of the compounds of formula (I) or pharmaceutically acid addition salts acceptable thereof for the treatment or prophylaxis of disorders of the central nervous system and disorders psychosomatic, including anxiety syndrome, particularly generalized anxiety disorders, panic disorder, disorder compulsive, social phobia, agoraphobia, phobias related to specific situations, stress disorders, disorders post-traumatic memory, alterations Cognitive, sexual dysfunction of origin in the nervous system central depression, schizophrenia, gastrointestinal diseases and cardiovascular diseases.
Es conocido a partir de la especificación de patente europea nº 376.607 y de la literatura técnica (A. Dekeyne, J.M. Rivet, A. Gobert, M.J. Millan: Neuropharmacology 40(7):899-910, 2001; J.S. Sprouse et al.: Neuropsychopharmacology 21(5):622-631, 1999; A. Newman-Tancredi et al., Eur. J. Pharmacol. 355(2-3):245-246, 1998) que los compuestos de la técnica anterior de tipo 1,3-dihidro-2H-indol-2-ona se unen selectivamente a receptores 5-HT_{1A} y de esta manera afectan al sistema nervioso central. En consecuencia, pueden utilizarse para el tratamiento de la depresión y los trastornos de ansiedad, y además las enfermedades cardiovasculares, gastrointestinales y renales.It is known from European Patent Specification No. 376,607 and technical literature (A. Dekeyne, JM Rivet, A. Gobert, MJ Millan: Neuropharmacology 40 (7): 899-910, 2001; JS Sprouse et al .: Neuropsychopharmacology 21 (5): 622-631, 1999; A. Newman-Tancredi et al. , Eur. J. Pharmacol. 355 (2-3): 245-246, 1998) than type 1 prior art compounds , 3-dihydro-2H-indole-2-one selectively bind to 5-HT1A receptors and thus affect the central nervous system. Consequently, they can be used for the treatment of depression and anxiety disorders, and also cardiovascular, gastrointestinal and kidney diseases.
La invención se basa en el inesperado reconocimiento de que los compuestos de fórmula general (I) ejercen una actividad ansiolítica pero no se unen a receptores 5-HT_{1A}. De esta manera, puede esperarse que carecen de los efectos secundarios negativos indicados anteriormente característicos de los ingredientes de unión de los receptores 5-HT_{1A}.The invention is based on the unexpected recognition that the compounds of general formula (I) exert an anxiolytic activity but do not bind to receptors 5-HT_ {1A}. In this way, it can be expected that lack the indicated negative side effects previously characteristic of the binding ingredients of 5-HT1A receptors.
La unión de los compuestos de fórmula general (I) a receptores 5-HT_{1A} se investigó siguiendo el procedimiento de Peroutka (S.J. Peroutka, J. Neurochem. 47:529, 1986).The binding of the compounds of the general formula (I) to 5-HT1A receptors was investigated following the Peroutka procedure (S.J. Peroutka, J. Neurochem. 47: 529, 1986).
Se determinaron las uniones de receptores a partir de preparaciones de membrana de córtex frontal aislado de ratas mediante la utilización de ligando 8-hidroxi-N,N-dipropil-2-amin-tetralina (8-OH-DPAT) tritiado. Para la determinación de la unión no específica se utilizó sulfato de serotonina-creatinina 10 \muM. Se aplicaron las condiciones siguientes: volumen de sangre de incubación: 250 \mul, temperatura de incubación: 25ºC, tiempo de incubación: 30 minutos. La reacción se terminó mediante la adición de 9 ml de tampón Tris-HCl helado 50 mM (pH=7,7) y filtración bajo vacío rápida utilizando papel de filtro de fibra de vidrio GF/B. Se midió la radioactividad de las hojas de filtro con ayuda de un espectrómetro de centelleo líquido.Receptor junctions were determined from frontal cortex membrane preparations isolated from rats by using ligand 8-hydroxy-N, N-dipropyl-2-amin-tetralin (8-OH-DPAT) tritiated. For the determination of non-specific binding was used sulfate 10 µM serotonin-creatinine. The following conditions: incubation blood volume: 250 µl, incubation temperature: 25 ° C, incubation time: 30 minutes. The reaction was terminated by the addition of 9 ml of buffer 50 mM frozen Tris-HCl (pH = 7.7) and low filtration Quick vacuum using GF / B fiberglass filter paper. Be measured the radioactivity of the filter sheets with the help of a liquid scintillation spectrometer.
La IC_{50} es la concentración por la que la diferencia entre la unión completa y la unión no específica en presencia de sulfato de serotonina-creatinina 10 \muM es de 50%. Los compuestos con un valor de IC_{50} inferior a 100 nmoles se consideraron efectivos en este ensayo. Se proporcionan los resultados en la Tabla 1.The IC 50 is the concentration by which the difference between complete binding and non-specific binding in presence of serotonin-creatinine sulfate 10 µM is 50%. Compounds with a lower IC 50 value at 100 nmoles were considered effective in this trial. Be provide the results in Table 1.
A partir de los resultados dados a conocer en la Tabla 1 puede observarse que los compuestos de ensayo no se unen a receptores 5-HT_{1A}.From the results disclosed in the Table 1 it can be seen that the test compounds do not bind to 5-HT1A receptors.
Se investigó el efecto ansiolítico de los compuestos según la invención en ratas según el ensayo denominado de laberinto radial elevado (S. Pelow, P. Chopin, S.E. File, J. Briley: Neurosci. Methods 14:149, 1985).The anxiolytic effect of the compounds according to the invention in rats according to the test called of raised radial labyrinth (S. Pelow, P. Chopin, S.E. File, J. Briley: Neurosci. Methods 14: 149, 1985).
Para los experimentos se utilizó una cruz de madera elevada a 50 cm por encima del suelo, de 15 cm de anchura con brazos de 100 cm de longitud. Los lados y extremos de los dos brazos de la cruz estaban provistos de paredes de 40 cm de altura, sin embargo, los brazos se encontraban abiertos al área central de 15 cm x 15 cm (brazos cerrados). Los otros dos brazos enfrentados no se encontraban rodeados por paredes (brazos abiertos).For the experiments a cross of wood raised 50 cm above the ground, 15 cm wide with arms 100 cm long. The sides and ends of both arms of the cross were provided with walls 40 cm high, however, the arms were open to the central area of 15 cm x 15 cm (closed arms). The other two arms facing each other They were not surrounded by walls (open arms).
Para los experimentos se utilizaron ratas Sprague-Dawley macho que pesaban 200 a 220 g. Los animales se dejaron en el área central del equipo 60 minutos después del tratamiento y se observaron los cuatro parámetros siguientes en el tiempo de ensayo de 5 minutos:Rats were used for the experiments Male Sprague-Dawley weighing 200 to 220 g. The Animals were left in the central area of the team 60 minutes after treatment and the four parameters were observed following in the test time of 5 minutes:
tiempo en los brazos abiertos (s),open arms time (s),
tiempo en los brazos cerrados (s),time in the closed arms (s),
número de entradas en los brazos abiertos,number of entries in open arms,
número de entradas en los brazos cerrados.number of entries in the closed arms.
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El efecto se expresó como porcentaje de incremento del tiempo en los brazos abiertos o número de entradas en los brazos abiertos. Se determinaron las MED (dosis efectivas mínimas) para cada compuesto. Los resultados se resumen en la Tabla 5.The effect was expressed as a percentage of increased time in open arms or number of entries in open arms MED were determined (effective doses minimum) for each compound. The results are summarized in the Table 5.
A partir de los datos de las tablas anteriores puede observarse que los compuestos de fórmula general (I) presentan un efecto ansiolítico significativo.From the data in the previous tables it can be seen that the compounds of general formula (I) they have a significant anxiolytic effect.
Basándose en los experimentos anteriores, los compuestos según la invención muestran una eficacia considerable en el tratamiento de trastornos del sistema nervioso central. Podrían demostrar ser particularmente adecuados para el tratamiento de trastornos de ansiedad, mezcla de ansiedad y depresión o en el caso de otros trastornos caracterizados por condiciones de estrés extremo que requieren la tranquilización del paciente. También pueden utilizarse para el tratamiento de enfermedades psicosomáticas, tales como la hipertensión de origen psíquico, úlcera gastrointestinal, colitis, asma, etc. En el caso de estos patrones clínicos, se puede suponer que en el fondo se encuentran estrés crónico, ansiedad y/o conflictos no tratados. Los nuevos compuestos según la invención inesperadamente no ejercen su actividad terapéutica favorable a través de receptores 5-HT_{1A}, de manera que puede se puede esperar que carecen de los efectos secundarios de los ingredientes activos que actúan sobre los receptores 5-HT_{1A}.Based on the previous experiments, the compounds according to the invention show considerable efficacy in the treatment of disorders of the central nervous system. Could prove to be particularly suitable for the treatment of anxiety disorders, mixture of anxiety and depression or in the case of other disorders characterized by stress conditions extreme requiring patient reassurance. Too can be used to treat diseases psychosomatic, such as hypertension of psychic origin, gastrointestinal ulcer, colitis, asthma, etc. In the case of these clinical patterns, it can be assumed that deep down are chronic stress, anxiety and / or untreated conflicts. The new ones compounds according to the invention unexpectedly do not exert their favorable therapeutic activity through receptors 5-HT_ {1A}, so that it can be expected that lack the side effects of active ingredients which act on the 5-HT1A receptors.
Se proporcionan detalles adicionales de la presente invención en los ejemplos siguientes sin limitar el alcance de protección a dichos ejemplos.Additional details of the present invention in the following examples without limiting the scope of protection to these examples.
Se disolvieron 1,68 g (0,01 moles) de 5-cloro-oxindol en 20 ml de etanol, y se añadió 1,0 g de níquel de Raney a la solución. Se dejó que reaccionase la mezcla de reacción en una autoclave a 100ºC durante 36 horas. A continuación, el catalizador se separó mediante filtración, el solvente se evaporó y el residuo se recristalizó a partir de una mezcla de hexano y acetato de etilo.1.68 g (0.01 mol) of 5-chloro-oxindole in 20 ml of ethanol, and 1.0 g of Raney nickel was added to the solution. It was left that the reaction mixture was reacted in an autoclave at 100 ° C for 36 hours Then the catalyst was separated by filtration, the solvent was evaporated and the residue was recrystallized from from a mixture of hexane and ethyl acetate.
Rendimiento: 0,86 g de polvos blancos (44%).Yield: 0.86 g of white powders (44%).
P.f.: 121ºC a 123ºC (hexano-acetato de etilo).Mp .: 121 ° C to 123 ° C (hexane-ethyl acetate).
IR (KBr): 3156, 1701 (C=O), 782 cm^{-1}.IR (KBr): 3156, 1701 (C = O), 782 cm -1.
RMN-^{1}H (CDCl_{3}): 9,27 (br s, 1H, NH), 7,21 (1H, s, H-4), 7,19 (d, 1H, J=8,8 Hz, H-6), 6,85 (d, 1H, J=8,1 Hz, H-7), 3,47 (t, 1H, J=5,5 Hz, H-3), 2,03 (m, 2H, CH_{2}), 0,92 (t, 3H, J=7,0 Hz, CH_{3}) ppm.1 H NMR (CDCl 3): 9.27 (br s, 1H, NH), 7.21 (1H, s, H-4), 7.19 (d, 1H, J = 8.8 Hz, H-6), 6.85 (d, 1H, J = 8.1 Hz, H-7), 3.47 (t, 1H, J = 5.5 Hz, H-3), 2.03 (m, 2H, CH2), 0.92 (t, 3H, J = 7.0 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}): 180,5, 140,4, 131,2, 127,8, 127,6, 124,5, 110,7, 47,5, 23,5, 9,9 ppm.NMR - 13 C (CDCl 3): 180.5, 140.4, 131.2, 127.8, 127.6, 124.5, 110.7, 47.5, 23.5, 9.9 ppm.
Análisis elemental de la fórmula C_{10}H_{10}ClNO (195,65).Elemental analysis of the formula C 10 H 10 ClNO (195.65).
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Se disolvió 3-etil oxindol (16,1 g, 0,10 moles) en 350 ml de acetonitrilo, la solución se enfrió a 0ºC y se introdujo una solución de N-bromosuccinimida (17,8 g, 0,10 moles) en 150 ml de acetonitrilo a la misma temperatura dentro de las 2 horas. La mezcla de reacción se agitó en primer lugar a 0ºC durante 1 hora y después a temperatura ambiente durante 3 horas. La solución se evaporó, la sustancia blanca se separó en forma cristalina con diclorometano y solución de NaOH 1 M, y la fase orgánica se extrajo nuevamente con agua alcalina con el fin de eliminar succinimida. La fase orgánica se secó sobre sulfato sódico, se filtró y se evaporó. La sustancia blanca separada se recristalizó a partir de una mezcla de heptano y acetato de etilo. Rendimiento: 15,24 g de polvos blancos (63%).3-ethyl oxindole (16.1) was dissolved g, 0.10 mol) in 350 ml of acetonitrile, the solution was cooled to 0 ° C and a solution of N-Bromosuccinimide (17.8 g, 0.10 mol) in 150 ml of acetonitrile at the same temperature within 2 hours. The reaction mixture was stirred first at 0 ° C for 1 hour and then at room temperature for 3 hours. The solution is evaporated, the white substance separated in crystalline form with dichloromethane and 1 M NaOH solution, and the organic phase was extracted again with alkaline water in order to remove succinimide. The The organic phase was dried over sodium sulfate, filtered and evaporated. The separated white substance was recrystallized from a mixture of heptane and ethyl acetate. Yield: 15.24 g of powders white (63%).
P.f.: 125ºC a 127ºC (heptano-acetato de etilo).Mp .: 125 ° C to 127 ° C (heptane-ethyl acetate).
IR (KBr): 3154, 1700 (C=O), 812 cm^{-1}.IR (KBr): 3154, 1700 (C = O), 812 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,90 (1H, s), 7,36-7,32 (2H, m), 6,81 (1H, d, J=8,9 Hz), 3,43 (1H, t, J=5,8 Hz), 2,03 (2H, q, J=7,4 Hz), 0,92 (3H, t, J=7,4 Hz) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.90 (1H, s), 7.36-7.32 (2H, m), 6.81 (1H, d, J = 8.9 Hz), 3.43 (1H, t, J = 5.8 Hz), 2.03 (2H, q, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 180,3, 140,8, 131,6, 130,7, 127,2, 114,9, 111,2, 47,2, 23,4, 9,9 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 180.3, 140.8, 131.6, 130.7, 127.2, 114.9, 111.2, 47.2, 23.4, 9.9 ppm.
Análisis elemental de la fórmula C_{10}H_{10}BrNO (240,10):Elemental analysis of the formula C 10 H 10 BrNO (240.10):
En un matraz enjuagado con argón 2,5 M se introdujo n-butil-litio (60 ml; 0,15 moles). Se añadieron 200 ml de THF, y la solución se enfrió en un baño de acetona-hielo seco a -78ºC. A esta temperatura, se introdujo bajo agitación una solución del 3-alquil oxindol apropiado (0,20 moles) en 250 ml de THF. La mezcla se agitó durante 10 minutos adicionales, se añadió gota a gota un dihaloalcano (1-bromo-4-clorobutano, 1-bromo-3-cloropropano, 1,5-dibromopentano o 1,6-dibromohexano; 0,50 moles) y se dejó que la solución se calentase hasta la temperatura ambiente. A continuación, se agitó adicionalmente durante 3 horas, y se introdujeron 20 ml de etanol con el fin de descomponer el exceso de butil-litio. La solución se destiló con un evaporador giratorio y el aceite residual se extrajo con agua y acetato de etilo. La fase orgánica se secó sobre sulfato sódico. El aceite residual se cristalizó mediante trituración con hexano. Los cristales blanquecinos separados se agitaron en 200 ml de hexano con el fin de eliminar el exceso de dihaloalcano, se filtraron y se lavaron con hexano. El producto se utilizó para reacciones adicionales sin recristalización. Pueden obtenerse muestras analíticas mediante recristalización a partir del solvente indicado.In a flask flask with 2.5 M argon, introduced n-butyllithium (60 ml; 0.15 moles). 200 ml of THF was added, and the solution cooled in a dry acetone-ice bath at -78 ° C. At this temperature, a solution of the Appropriate 3-alkyl oxindole (0.20 mol) in 250 ml of THF. The mixture was stirred for an additional 10 minutes, added drop by drop a dihaloalkane (1-Bromo-4-Chlorobutane, 1-bromo-3-chloropropane, 1,5-dibromopentane or 1,6-dibromohexane; 0.50 moles) and the solution is heated to room temperature. TO then it was stirred further for 3 hours, and it was introduced 20 ml of ethanol in order to break down the excess of butyl lithium The solution was distilled with a rotary evaporator and the residual oil was extracted with water and ethyl acetate. The organic phase was dried over sodium sulfate. He residual oil was crystallized by trituration with hexane. The separate whitish crystals were stirred in 200 ml of hexane in order to remove excess dihaloalkane, they were filtered and washed with hexane. The product was used for reactions additional without recrystallization. Samples can be obtained analytical by recrystallization from solvent indicated.
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-clorobutano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chlorobutane.
P.f.: 104ºC a 105ºC (hexano-acetato de etilo)Mp .: 104 ° C to 105 ° C (hexane-ethyl acetate)
IR (KBr): 3181, 2941, 1700, 1306, 755 cm^{-1}.IR (KBr): 3181, 2941, 1700, 1306, 755 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,57 (br s, 1H, NH), 7,21 (dt, 1H, J=7,6, 1,5 Hz, H-6), 7,12 (d, 1H, J=7,4 Hz, H-4), 7,06 (dt, 1H, J=7,5, 1,0 Hz, H-5), 6,92 (d, 1H, J=7,7 Hz, H-7), 3,39 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,96-1,84 (m, 2H, CH_{2}), 1,83-1,74 (m, 2H, CH_{2}), 1,74-1,60 (m, 2H, CH_{2}), 1,24-1,18 (m, 1H), 1,08-1,03 (m, 1H), 0,64 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.57 (br s, 1H, NH), 7.21 (dt, 1H, J = 7.6, 1.5 Hz, H-6), 7.12 (d, 1H, J = 7.4 Hz, H-4), 7.06 (dt, 1H, J = 7.5, 1.0 Hz, H-5), 6.92 (d, 1H, J = 7.7 Hz, H-7), 3.39 (t, 2H, J = 6.7 Hz, CH 2 Cl), 1.96-1.84 (m, 2H, CH2), 1.83-1.74 (m, 2H, CH2), 1.74-1.60 (m, 2H, CH2), 1.24-1.18 (m, 1H), 1.08-1.03 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,4, 141,2, 132,3, 127,7, 123,0, 122,5, 109,6, 54,1, 44,4, 36,8, 32,7, 31,0, 21,8, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.4, 141.2, 132.3, 127.7, 123.0, 122.5, 109.6, 54.1, 44.4, 36.8, 32.7, 31.0, 21.8, 8.5 ppm.
Análisis elemental de la fórmula C_{14}H_{18}ClNO (251,76):Elemental analysis of the formula C 14 H 18 ClNO (251.76):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-cloro-butano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chloro-butane.
P.f.: 96ºC a 97ºC (hexano-acetato de etilo).Mp .: 96 ° C to 97 ° C (hexane-ethyl acetate).
IR (KBr): 3159, 1716, 817 cm^{-1}.IR (KBr): 3159, 1716, 817 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,99 (br s, 1H, NH), 6,95-6,85 (m, 3H), 3,40 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,97-1,88 (m, 2H, CH_{2}), 1,83-1,75 (m, 2H, CH_{2}), 1,73-1,62 (m, 2H), 1,25-1,20 (m, 1H), 1,09-1,04 (m, 1H), 0,65 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.99 (br s, 1H, NH), 6.95-6.85 (m, 3H), 3.40 (t, 2H, J = 6.7 Hz, CH2Cl), 1.97-1.88 (m, 2H, CH2), 1.83-1.75 (m, 2H, CH2), 1.73-1.62 (m, 2H), 1.25-1.20 (m, 1H), 1.09-1.04 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,5, 159,3 (d, J=240,7 Hz), 137,2, 134,1 (d, J=7,6 Hz), 114,1 (d, J=23,7 Hz), 111,9 (d, J=24,4 Hz), 110,2 (d, J=2,0 Hz), 54,8 (d, J=2,0 Hz), 44,4, 36,8, 32,5, 31,0, 21,7, 8,4 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.5, 159.3 (d, J = 240.7 Hz), 137.2, 134.1 (d, J = 7.6 Hz), 114.1 (d, J = 23.7 Hz), 111.9 (d, J = 24.4 Hz), 110.2 (d, J = 2.0 Hz), 54.8 (d, J = 2.0 Hz), 44.4, 36.8, 32.5, 31.0, 21.7, 8.4 ppm.
Análisis elemental de la fórmula C_{14}H_{17}ClFNO (269,75):Elemental analysis of the formula C 14 H 17 ClFNO (269.75):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-6-fluoro-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-clorobutano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chlorobutane.
P.f.: 95ºC a 97ºC (hexano-acetato de etilo).Mp .: 95 ° C to 97 ° C (hexane-ethyl acetate).
IR (KBr): 3195, 1728, 1132 cm^{-1}.IR (KBr): 3195, 1728, 1132 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,34 (br s, 1H, NH), 7,05 (dd, 1H, J=8,1, 5,3 Hz, H-4), 6,75 (ddd, 1H, J=9,6, 8,1, 2,4 Hz, H-5), 6,71 (dd, 1H, J=8,8, 2,4 Hz, H-7), 3,44 (t, 2H, J=6,7 Hz, CH_{2}Cl), 2,00-1,70 (m, 4H, 2 x CH_{2}), 1,70-1,60 (m, 2H, CH_{2}), 1,23-1,18 (m, 1H), 1,08-1,04 (m, 1H), 0,64 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.34 (br s, 1H, NH), 7.05 (dd, 1H, J = 8.1, 5.3 Hz, H-4), 6.75 (ddd, 1H, J = 9.6, 8.1, 2.4 Hz, H-5), 6.71 (dd, 1H, J = 8.8, 2.4 Hz, H-7), 3.44 (t, 2H, J = 6.7 Hz, CH2Cl), 2.00-1.70 (m, 4H, 2 x CH2), 1.70-1.60 (m, 2H, CH2), 1.23-1.18 (m, 1H), 1.08-1.04 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 183,3, 162,5 (d, J=244,1 Hz), 142,5 (d, J=7,8 Hz), 127,5 (d, J=13,0 Hz), 123,8 (d, J=9,5 Hz), 108,8 (d, J=22,5 Hz), 98,5 (d, J=27,4 Hz), 53,8, 44,4, 36,8, 32,5, 31,0, 21,6, 8,4 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 183.3, 162.5 (d, J = 244.1 Hz), 142.5 (d, J = 7.8 Hz), 127.5 (d, J = 13.0 Hz), 123.8 (d, J = 9.5 Hz), 108.8 (d, J = 22.5 Hz), 98.5 (d, J = 27.4 Hz), 53.8, 44.4, 36.8, 32.5, 31.0, 21.6, 8.4 ppm.
Análisis elemental de la fórmula C_{14}H_{17}ClFNO (269,75).Elemental analysis of the formula C 14 H 17 ClFNO (269.75).
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-5-metil-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-clorobutano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chlorobutane.
P.f.: 79ºC a 80ºC (hexano).Mp .: 79 ° C to 80 ° C (hexane).
IR (KBr): 3286, 1719 cm^{-1}.IR (KBr): 3286, 1719 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,70 (br s, 1H, NH), 7,00 (d, 1H, J=7,8 Hz, H-6), 6,92 (s, 1H, H-4), 6,81 (d, 1H, J=7,9 Hz, H-7), 3,39 (t, 2H, J=6,8 Hz, CH_{2}Cl), 1,95-1,85 (m, 2H), 1,82-1,70 (m, 2H), 1,70-1,58 (m, 2H), 1,30-1,12 (m, 1H), 1,10-0,98 (m, 1H), 0,63 (t, 3H, J=7,3 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.70 (br s, 1H, NH), 7.00 (d, 1H, J = 7.8 Hz, H-6), 6.92 (s, 1H, H-4), 6.81 (d, 1H, J = 7.9 Hz, H-7), 3.39 (t, 2H, J = 6.8 Hz, CH 2 Cl), 1.95-1.85 (m, 2H), 1.82-1.70 (m, 2H), 1.70-1.58 (m, 2H), 1.30-1.12 (m, 1H), 1.10-0.98 (m, 1H), 0.63 (t, 3H, J = 7.3 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,5, 138,8, 132,4, 131,9, 128,0, 123,7, 109,3, 54,1, 44,4, 36,9, 32,7, 31,0, 21,8, 8,4 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.5, 138.8, 132.4, 131.9, 128.0, 123.7, 109.3, 54.1, 44.4, 36.9, 32.7, 31.0, 21.8, 8.4 ppm.
Análisis elemental de la fórmula C_{15}H_{20}ClNO (265,79):Elemental analysis of the formula C 15 H 20 ClNO (265.79):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-7-metil-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-clorobutano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-7-methyl-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chlorobutane.
P.f.: 112ºC a 113ºC (hexano-acetato de etilo).Mp .: 112 ° C to 113 ° C (hexane-ethyl acetate).
IR (KBr): 3181, 1703 (C=O), 748 cm^{-1}.IR (KBr): 3181, 1703 (C = O), 748 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,63 (3H, t, J=7,4 Hz), 1,07-1,02 (1H, m), 1,25-1,17 (1H, m), 1,70-1,60 (2H, m), 1,81-1,72 (2H, m), 1,96-1,86 (2H, m), 2,31 (3H, s), 3,36 (2H, t, J=6,8 Hz), 6,94 (1H, dd, J=1,7, 7,3 Hz), 6,97 (1H, t, J=7,3 Hz), 7,03 (1H, dd, J=1,4, 7,2 Hz), 9,4 (1H, br s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 1.07-1.02 (1H, m), 1.25-1.17 (1H, m), 1.70-1.60 (2H, m), 1.81-1.72 (2H, m), 1.96-1.86 (2H, m), 2.31 (3H, s), 3.36 (2H, t, J = 6.8 Hz), 6.94 (1H, dd, J = 1.7, 7.3 Hz), 6.97 (1H, t, J = 7.3 Hz), 7.03 (1H, dd, J = 1.4, 7.2 Hz), 9.4 (1H, br s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 8,5, 16,5, 21,8, 31,0, 32,7, 36,8, 44,4, 54,4, 119,1, 120,3, 122,4, 129,1, 131,9, 140,1, 183,1 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 8.5, 16.5, 21.8, 31.0, 32.7, 36.8, 44.4, 54.4, 119.1, 120.3, 122.4, 129.1, 131.9, 140.1, 183.1 ppm.
Análisis elemental de la fórmula C_{15}H_{20}ClNO (265,79):Elemental analysis of the formula C 15 H 20 ClNO (265.79):
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Se preparó el compuesto del título según el procedimiento "A", partiendo de 3-etil-1,3-dihidro-2H-indol-2-ona y 1-bromo-3-cloropropano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-1,3-dihydro-2H-indole-2-one Y 1-Bromo-3-chloropropane.
IR (KBr): 3183, 1701, 751 cm^{-1}.IR (KBr): 3183, 1701, 751 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,15 (br s, 1H, NH), 7,23 (dt, 1H, J=7,7, 1,3 Hz, H-6), 7,14 (d, 1H, J=6,8 Hz, H-4), 7,06 (dt, 1H, J=7,4, 0,9 Hz, H-5), 6,95 (d, 1H, J=7,7 Hz, H-7), 3,48-3,36 (m, 2H, CH_{2}Cl), 2,02-1,93 (m, 3H), 1,85-1,78 (m, 1H), 1,66-1,54 (m, 1H), 1,44-1,30 (m, 1H), 0,65 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.15 (br s, 1H, NH), 7.23 (dt, 1H, J = 7.7, 1.3 Hz, H-6), 7.14 (d, 1H, J = 6.8 Hz, H-4), 7.06 (dt, 1H, J = 7.4, 0.9 Hz, H-5), 6.95 (d, 1H, J = 7.7 Hz, H-7), 3.48-3.36 (m, 2H, CH 2 Cl), 2.02-1.93 (m, 3H), 1.85-1.78 (m, 1H), 1.66-1.54 (m, 1H), 1.44-1.30 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,6, 141,3, 132,0, 127,9, 123,0, 122,6, 109,8, 53,7, 44,8, 34,8, 31,0, 27,5, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.6, 141.3, 132.0, 127.9, 123.0, 122.6, 109.8, 53.7, 44.8, 34.8, 31.0, 27.5, 8.5 ppm.
Análisis elemental de la fórmula C_{13}H_{16}ClNO (237,73):Elemental analysis of the formula C 13 H 16 ClNO (237.73):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-1,3-dihidro-2H-indol-2-ona y 1,5-dibromopentano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-1,3-dihydro-2H-indole-2-one and 1,5-dibromopentane.
P.f.: 77ºC a 78ºC (hexano).Mp .: 77 ° C to 78 ° C (hexane).
IR (KBr): 3290, 1718, 772 cm^{-1}.IR (KBr): 3290, 1718, 772 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,11 (br s, 1H, NH), 7,20 (dt, 1H, J=7,6, 1,4 Hz, H-6), 7,11 (d, 1H, J=7,3 Hz, H-4), 7,05 (dt, 1H, J=7,4, 1,0 Hz, H-5), 6,94 (d, 1H, J=7,4 Hz), 3,27 (t, 2H, J=6,9 Hz, CH_{2}Br), 1,98-1,86 (m, 2H, CH_{2}), 1,84-1,74 (m, 2H, CH_{2}), 1,71 (quinteto, 2H, J=7,2 Hz, CH_{2}), 1,38-1,24 (m, 2H), 1,18-1,04 (m, 1H), 0,96-0,84 (m, 1H), 0,63 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.11 (br s, 1H, NH), 7.20 (dt, 1H, J = 7.6, 1.4 Hz, H-6), 7.11 (d, 1H, J = 7.3 Hz, H-4), 7.05 (dt, 1H, J = 7.4, 1.0 Hz, H-5), 6.94 (d, 1H, J = 7.4 Hz), 3.27 (t, 2H, J = 6.9 Hz, CH2 Br), 1.98-1.86 (m, 2H, CH2), 1.84-1.74 (m, 2H, CH2), 1.71 (quintet, 2H, J = 7.2 Hz, CH2), 1.38-1.24 (m, 2H), 1.18-1.04 (m, 1H), 0.96-0.84 (m, 1H), 0.63 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,9, 141,4, 132,5, 127,6, 122,9, 122,4, 109,7, 54,2, 37,4, 33,6, 32,4, 31,0, 28,2, 23,4, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.9, 141.4, 132.5, 127.6, 122.9, 122.4, 109.7, 54.2, 37.4, 33.6, 32.4, 31.0, 28.2, 23.4, 8.5 ppm.
Análisis elemental de la fórmula C_{15}H_{20}BrNO (310,24):Elemental analysis of the formula C 15 H 20 BrNO (310.24):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-isobutil-1,3-dihidro-2H-indol-2-ona y 1-bromo-4-clorobutano.The title compound was prepared according to "A" procedure, starting from 3-isobutyl-1,3-dihydro-2H-indole-2-one Y 1-bromo-4-chlorobutane.
P.f.: 124ºC a 125ºC (hexano-acetato de etilo).Mp .: 124 ° C to 125 ° C (hexane-ethyl acetate).
IR (KBr): 3208, 1713, 747 cm^{-1}.IR (KBr): 3208, 1713, 747 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,02 (br s, 1H, NH), 7,21 (dt, 1H, J=7,5, 1,4 Hz, H-6), 7,11 (td, 1H, J=7,4, 0,6 Hz, H-4), 7,04 (dt, 1H, J=7,4, 1,0 Hz, H-5), 6,96 (d, 1H, J=7,7 Hz, H-7), 3,37 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,95-1,70 (m, 4H, 2 x CH_{2}), 1,70-1,58 (m, 2H, CH_{2}), 1,38-1,30 (m, 1H), 1,23-1,17 (m, 1H), 1,02-0,98 (m, 1H), 0,73 (d, 3H, J=6,6 Hz, CH_{3}), 0,61 (d, 3H, J=6,6 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.02 (br s, 1H, NH), 7.21 (dt, 1H, J = 7.5, 1.4 Hz, H-6), 7.11 (td, 1H, J = 7.4, 0.6 Hz, H-4), 7.04 (dt, 1H, J = 7.4, 1.0 Hz, H-5), 6.96 (d, 1H, J = 7.7 Hz, H-7), 3.37 (t, 2H, J = 6.7 Hz, CH2Cl), 1.95-1.70 (m, 4H, 2 x CH2), 1.70-1.58 (m, 2H, CH2), 1.38-1.30 (m, 1H), 1.23-1.17 (m, 1H), 1.02-0.98 (m, 1H), 0.73 (d, 3H, J = 6.6 Hz, CH 3), 0.61 (d, 3H, J = 6.6 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 183,1, 141,1, 132,6, 127,7, 123,3, 122,3, 109,8, 53,0, 46,3, 44,4, 39,2, 32,6, 25,3, 24,2, 23,6, 21,1 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 183.1, 141.1, 132.6, 127.7, 123.3, 122.3, 109.8, 53.0, 46.3, 44.4, 39.2, 32.6, 25.3, 24.2, 23.6, 21.1 ppm.
Análisis elemental de la fórmula C_{16}H_{22}ClNO (279,81):Elemental analysis of the formula C 16 H 22 ClNO (279.81):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 1,5-dibromopentano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one and 1,5-dibromopentane.
P.f.: 82ºC a 83ºC (hexano).Mp .: 82 ° C to 83 ° C (hexane).
IR (KBr): 3293, 1720, 1690, 1175, 817 cm^{-1}.IR (KBr): 3293, 1720, 1690, 1175, 817 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 7,96 (br s, 1H, NH), 6,92 (dt, 1H, J=8,8, 2,6 Hz, H-6), 6,86 (dd, 1H, J=8,0, 2,6 Hz, H-4), 6,82 (dd, 1H, J=8,4, 4,3 Hz, H-7), 3,30 (t, 2H, J=6,9 Hz, CH_{2}Br), 1,96-1,87 (m, 2H, CH_{2}), 1,80-1,68 (m, 4H, 2 x CH_{2}), 1,40-1,25 (m, 2H, CH_{2}), 1,18-1,04 (m, 1H), 0,96-0,84 (m, 1H), 0,64 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 7.96 (br s, 1H, NH), 6.92 (dt, 1H, J = 8.8, 2.6 Hz, H-6), 6.86 (dd, 1H, J = 8.0, 2.6 Hz, H-4), 6.82 (dd, 1H, J = 8.4, 4.3 Hz, H-7), 3.30 (t, 2H, J = 6.9 Hz, CH2 Br), 1.96-1.87 (m, 2H, CH2), 1.80-1.68 (m, 4H, 2 x CH2), 1.40-1.25 (m, 2H, CH2), 1.18-1.04 (m, 1H), 0.96-0.84 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 181,8, 159,3 (d, J=240,7 Hz), 136,9, 134,4 (d, J=8,0 Hz), 114,0 (d, J=23,3 Hz), 111,0 (d, J=24,4 Hz), 109,9 (d, J=8,0 Hz), 54,7, 37,5, 33,6, 32,4, 31,1, 28,2, 23,5, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 181.8, 159.3 (d, J = 240.7 Hz), 136.9, 134.4 (d, J = 8.0 Hz), 114.0 (d, J = 23.3 Hz), 111.0 (d, J = 24.4 Hz), 109.9 (d, J = 8.0 Hz), 54.7, 37.5, 33.6, 32.4, 31.1, 28.2, 23.5, 8.5 ppm.
Análisis elemental de la fórmula C_{15}H_{19}BrFNO (328,23):Elemental analysis of the formula C 15 H 19 BrFNO (328.23):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-5-metil-1,3-dihidro-2H-indol-2-ona y 1,5-dibromopentano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-5-methyl-1,3-dihydro-2H-indole-2-one and 1,5-dibromopentane.
P.f.: 72ºC a 73ºC (hexano).Mp .: 72 ° C to 73 ° C (hexane).
IR (KBr): 3262, 1726, 1694, 812 cm^{-1}.IR (KBr): 3262, 1726, 1694, 812 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 7,55 (br s, 1H, NH), 7,00 (d, 1H, J=7,9 Hz, H-6), 6,92 (s, 1H, H-4), 6,75 (d, 1H, J=7,8 Hz, H-7), 3,30 (t, 2H, J=6,8 Hz, CH_{2}Br), 1,94-1,84 (m, 2H, CH_{2}), 1,79-1,68 (m, 4H, 2 x CH_{2}), 1,35-1,24 (m, 2H, CH_{2}), 1,24-1,13 (m, 1H), 0,93-0,84 (m, 1H), 0,63 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 7.55 (br s, 1H, NH), 7.00 (d, 1H, J = 7.9 Hz, H-6), 6.92 (s, 1H, H-4), 6.75 (d, 1H, J = 7.8 Hz, H-7), 3.30 (t, 2H, J = 6.8 Hz, CH 2 Br), 1.94-1.84 (m, 2H, CH 2), 1.79-1.68 (m, 4H, 2 x CH2), 1.35-1.24 (m, 2H, CH2), 1.24-1.13 (m, 1H), 0.93-0.84 (m, 1H), 0.63 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 181,8, 159,3 (d, J=240,7 Hz), 136,9, 134,4 (d, J=8,0 Hz), 114,0 (d, J=23,3 Hz), 111,0 (d, J=24,4 Hz), 109,9 (d, J=8,0 Hz), 54,7, 37,5, 33,6, 32,4, 31,1, 28,2, 23,5, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 181.8, 159.3 (d, J = 240.7 Hz), 136.9, 134.4 (d, J = 8.0 Hz), 114.0 (d, J = 23.3 Hz), 111.0 (d, J = 24.4 Hz), 109.9 (d, J = 8.0 Hz), 54.7, 37.5, 33.6, 32.4, 31.1, 28.2, 23.5, 8.5 ppm.
Análisis elemental de la fórmula C_{16}H_{22}BrNO (324,26):Elemental analysis of the formula C 16 H 22 BrNO (324.26):
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El compuesto del título se preparó según el procedimiento "A", partiendo de 3-etil-6-fluoro-1,3-dihidro-2H-indol-2-ona y 1,5-dibromopentano.The title compound was prepared according to "A" procedure, starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one and 1,5-dibromopentane.
P.f.: 95ºC a 96ºC (hexano).Mp .: 95 ° C to 96 ° C (hexane).
IR (KBr): 3300, 1722, 857 cm^{-1}.IR (KBr): 3300, 1722, 857 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,24 (br s, 1H, NH), 7,01 (dd, 1H, J=8,1, 5,3 Hz, H-5), 6,72 (ddd, 1H, J=9,6, 8,2, 2,3 Hz, H-5), 6,68 (d, 1H, J=8,, 2,3 Hz, H-7), 3,26 (t, 2H, J=7,4 Hz, CH_{2}Br), 1,92-1,83 (m, 2H, CH_{2}), 1,80-1,65 (m, 4H, 2 x CH_{2}), 1,35-1,25 (m, 2H, CH_{2}), 1,09-1,00 (m, 1H), 0,92-0,84 (m, 1H), 0,60 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.24 (br s, 1H, NH), 7.01 (dd, 1H, J = 8.1, 5.3 Hz, H-5), 6.72 (ddd, 1H, J = 9.6, 8.2, 2.3 Hz, H-5), 6.68 (d, 1H, J = 8 ,, 2.3 Hz, H-7), 3.26 (t, 2H, J = 7.4 Hz, CH2 Br), 1.92-1.83 (m, 2H, CH2), 1.80-1.65 (m, 4H, 2 x CH2), 1.35-1.25 (m, 2H, CH2), 1.09-1.00 (m, 1H), 0.92-0.84 (m, 1H), 0.60 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 183,3, 162,4 (d, J=244,1 Hz), 142,5 (d, J=11,8 Hz), 127,7 (d, J=3,1 Hz), 123,8 (d, J=9,9 Hz), 108,7 (d, J=22,1 Hz), 98,4 (d, J=27,1 Hz), 53,9, 37,4, 33,6, 32,3, 31,0, 28,2, 23,4, 8,4 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 183.3, 162.4 (d, J = 244.1 Hz), 142.5 (d, J = 11.8 Hz), 127.7 (d, J = 3.1 Hz), 123.8 (d, J = 9.9 Hz), 108.7 (d, J = 22.1 Hz), 98.4 (d, J = 27.1 Hz), 53.9, 37.4, 33.6, 32.3, 31.0, 28.2, 23.4, 8.4 ppm.
Análisis elemental de la fórmula C_{15}H_{19}BrFNO (328,23):Elemental analysis of the formula C 15 H 19 BrFNO (328.23):
El compuesto haloalquilo (5 mmoles) se disolvió en 15 ml de ácido acético glacial, la solución se enfrió hasta iniciarse la separación del ácido acético glacial (14ºC a 16ºC) y se introdujo una solución de 0,5 ml (5,7 mmoles) de cloruro de sulfurilo en 5 ml de ácido acético glacial. La mezcla se agitó durante 2 horas a la misma temperatura y después se pipeteó sobre agua helada. La sustancia blanca separada se filtró, se lavó con agua y hexano, se secó y se utilizó para la reacción de acoplamiento sin purificación. Las muestras analíticas pueden obtenerse mediante recristalización a partir del solvente indicado.The haloalkyl compound (5 mmol) was dissolved in 15 ml of glacial acetic acid, the solution was cooled to start the separation of glacial acetic acid (14ºC to 16ºC) and introduced a solution of 0.5 ml (5.7 mmol) of chloride sulfuryl in 5 ml of glacial acetic acid. The mixture was stirred. for 2 hours at the same temperature and then pipetted over frozen water. The separated white substance was filtered, washed with water and hexane, dried and used for the coupling reaction without purification Analytical samples can be obtained by recrystallization from the indicated solvent.
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El compuesto del título se preparó según el procedimiento "B", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-onaThe title compound was prepared according to procedure "B", starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one
P.f.: 116ºC a 117ºC (hexano-acetato de etilo)Mp .: 116 ° C to 117 ° C (hexane-ethyl acetate)
IR (KBr): 3285, 1717, 818 cm^{-1}.IR (KBr): 3285, 1717, 818 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,72 (br s, 1H, NH), 7,15 (dd, 1H, J=8,2, 2,1, Hz, H-6), 7,12 (d, 1H, J=2,1 Hz, H-4), 6,86 (d, 1H, J=8,2 Hz, H-7), 3,41 (t, 2H, J=6,7 Hz, CH_{2}Cl), 2,00-1,86 (m, 2H, CH_{2}), 1,84-1,74 (m, 2H, CH_{2}), 1,74-1,60 (m, 2H), 1,29-1,15 (m, 1H), 1,12-0,95 (m, 1H), 0,65 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.72 (br s, 1H, NH), 7.15 (dd, 1H, J = 8.2, 2.1, Hz, H-6), 7.12 (d, 1H, J = 2.1 Hz, H-4), 6.86 (d, 1H, J = 8.2 Hz, H-7), 3.41 (t, 2H, J = 6.7 Hz, CH 2 Cl), 2.00-1.86 (m, 2H, CH 2), 1.84-1.74 (m, 2H, CH2), 1.74-1.60 (m, 2H), 1.29-1.15 (m, 1H), 1.12-0.95 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,0, 139,8, 134,2, 127,9, 127,8, 123,4, 110,7, 54,5, 44,4, 36,8, 32,5, 31,0, 21,7, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.0, 139.8, 134.2, 127.9, 127.8, 123.4, 110.7, 54.5, 44.4, 36.8, 32.5, 31.0, 21.7, 8.5 ppm.
Análisis elemental de la fórmula C_{14}H_{17}Cl_{2}NO (286,20):Elemental analysis of the formula C 14 H 17 Cl 2 NO (286.20):
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El compuesto del título se preparó según el procedimiento "B", partiendo de 3-(3-cloropropil)-3-etil-1,3-dihidro-2H-indol-2-ona.The title compound was prepared according to procedure "B", starting from 3- (3-Chloropropyl) -3-ethyl-1,3-dihydro-2H-indole-2-one.
P.f.: 105ºC a 107ºC (hexano).Mp .: 105 ° C to 107 ° C (hexane).
IR (KBr): 3221, 2963, 1700 (C=O), 1677, 1474 cm^{-1}.IR (KBr): 3221, 2963, 1700 (C = O), 1677, 1474 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,15 (br s, 1H, NH), 7,21 (dd, 1H, J=8,2, 2,1 Hz, H-6), 7,12 (d, 1H, J=2,0 Hz, H-4), 6,88 (d, 1H, J=8,2 Hz, H-7), 3,43-3,39 (m, 2H, CH_{2}Cl), 2,10-1,77 (m, 4H, 2 x CH_{2}), 1,62-1,55 (m, 1H), 1,42-1,38 (m, 1H), 0,66 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.15 (br s, 1H, NH), 7.21 (dd, 1H, J = 8.2, 2.1 Hz, H-6), 7.12 (d, 1H, J = 2.0 Hz, H-4), 6.88 (d, 1H, J = 8.2 Hz, H-7), 3.43-3.39 (m, 2H, CH2Cl), 2.10-1.77 (m, 4H, 2 x CH2), 1.62-1.55 (m, 1H), 1.42-1.38 (m, 1H), 0.66 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,1, 139,8, 133,9, 128,1 128,0, 123,5, 110,8, 54,1, 44,6, 34,7, 30,9, 27,5, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.1, 139.8, 133.9, 128.1 128.0, 123.5, 110.8, 54.1, 44.6, 34.7, 30.9, 27.5, 8.5 ppm.
Análisis elemental de la fórmula C_{13}H_{15}Cl_{2}NO (272,18):Elemental analysis of the formula C 13 H 15 Cl 2 NO (272.18):
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El compuesto del título se preparó según el procedimiento "B", partiendo de 6-fluoro-3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona.The title compound was prepared according to procedure "B", starting from 6-fluoro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one.
P.f.: 131ºC a 133ºC (hexano-acetato de etilo).Mp .: 131 ° C to 133 ° C (hexane-ethyl acetate).
IR (KBr): 3289, 1720, 1143 cm^{-1}.IR (KBr): 3289, 1720, 1143 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,90 (br s, 1H, NH), 7,12 (d, 1H, J=7,1 H-4), 6,79 (d, 1H, J=8,8 Hz, H-7), 3,42 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,96-1,84 (m, 2H, CH_{2}), 1,80-1,63 (m, 4H, 2 x CH_{2}), 1,30-1,20 (m, 1H), 1,20-1,04 (m, 1H), 0,65 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.90 (br s, 1H, NH), 7.12 (d, 1H, J = 7.1 H-4), 6.79 (d, 1H, J = 8.8 Hz, H-7), 3.42 (t, 2H, J = 6.7 Hz, CH2Cl), 1.96-1.84 (m, 2H, CH2), 1.80-1.63 (m, 4H, 2 x CH2), 1.30-1.20 (m, 1H), 1.20-1.04 (m, 1H), 0.65 (t, 3H, J = 7.4 Hz, CH3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,3, 157,6 (d, J=247,2 Hz), 140,9 (d, J=11,1 Hz), 128,8 (d, J=3,8 Hz), 124,8, 114,3 (d, J=18,3 Hz), 99,5 (d, J=26,7 Hz), 54,2, 44,3, 36,8, 32,4, 31,0, 21,6, 8,4 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.3, 157.6 (d, J = 247.2 Hz), 140.9 (d, J = 11.1 Hz), 128.8 (d, J = 3.8 Hz), 124.8, 114.3 (d, J = 18.3 Hz), 99.5 (d, J = 26.7 Hz), 54.2, 44.3, 36.8, 32.4, 31.0, 21.6, 8.4 ppm.
Análisis elemental de la fórmula C_{14}H_{16}Cl_{2}FNO (304,19):Elemental analysis of the formula C 14 H 16 Cl 2 FNO (304.19):
Se disolvió el compuesto cloroalquilo en 80 ml (40 mmoles) de ácido acético glacial, se introdujeron 9,6 ml (120 mmoles) de cloruro de sulfurilo a temperatura ambiente y la solución se mantuvo a 60ºC durante 3 horas. A continuación, la mezcla de reacción se enfrió, se vertió sobre hielo y se extrajo con éter dietílico. La fase éter se extrajo dos veces con 10% en volumen de solución de NaOH, se secó sobre sulfato sódico y se evaporó. El aceite amarillo pálido extraído de esta manera se trituró con hexano, se separó la sustancia blanca en forma cristalina y se agitó en hexano, se filtró, se lavó con hexano, se secó nuevamente y se utilizó para la reacción de acoplamiento sin purificación. Pueden obtenerse muestras analíticas a partir de los compuestos dados mediante recristalización a partir de los solventes indicados.The chloroalkyl compound was dissolved in 80 ml (40 mmol) of glacial acetic acid, 9.6 ml (120 mmoles) of sulfuryl chloride at room temperature and the solution It was maintained at 60 ° C for 3 hours. Then the mixture of reaction was cooled, poured onto ice and extracted with ether diethyl The ether phase was extracted twice with 10% by volume of NaOH solution, dried over sodium sulfate and evaporated. He pale yellow oil extracted in this way was triturated with hexane, the white substance was separated in crystalline form and stirred in hexane, filtered, washed with hexane, dried again and It was used for the coupling reaction without purification. Analytical samples can be obtained from the compounds given by recrystallization from solvents indicated.
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El compuesto del título se preparó según el procedimiento "C", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona.The title compound was prepared according to "C" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one.
P.f.: 65ºC a 67ºC (hexano).Mp .: 65 ° C to 67 ° C (hexane).
IR (KBr): 3165, 2964, 1713 (C=O), 1455 cm^{-1}.IR (KBr): 3165, 2964, 1713 (C = O), 1455 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,38 (br s, 1H, NH), 7,20 (d, 1H, J=1,9 Hz, H-6), 6,97 (d, 1H, J=1,8 Hz, H-4), 3,38 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,95-1,84 (m, 2H, CH_{2}), 1,76-1,60 (m, 4H, 2 x CH_{2}), 1,19-1,16 (m, 1H), 1,04-0,96 (m, 1H), 0,62 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.38 (br s, 1H, NH), 7.20 (d, 1H, J = 1.9 Hz, H-6), 6.97 (d, 1H, J = 1.8 Hz, H-4), 3.38 (t, 2H, J = 6.7 Hz, CH2Cl), 1.95-1.84 (m, 2H, CH2), 1.76-1.60 (m, 4H, 2 x CH2), 1.19-1.16 (m, 1H), 1.04-0.96 (m, 1H), 0.62 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 180,5, 137,7, 135,1, 128,3, 127,6, 121,9, 115,7, 55,7, 44,3, 36,8, 32,5, 31,0, 21,7, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 180.5, 137.7, 135.1, 128.3, 127.6, 121.9, 115.7, 55.7, 44.3, 36.8, 32.5, 31.0, 21.7, 8.5 ppm.
Análisis elemental de la fórmula C_{16}H_{22}ClNO (279,81):Elemental analysis of the formula C 16 H 22 ClNO (279.81):
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El compuesto del título se preparó según el procedimiento "C", partiendo de 3-(4-clorobutil)-3-isobutil-1,3-dihidro-2H-indol-2-ona.The title compound was prepared according to "C" procedure, starting from 3- (4-Chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indole-2-one.
P.f.: 93ºC a 94ºC (hexano).Mp .: 93 ° C to 94 ° C (hexane).
IR (KBr): 3144, 1719, 1459 cm^{-1}.IR (KBr): 3144, 1719, 1459 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,49 (br s, 1H, NH), 7,24 (dt, 1H, J=1,9 Hz, H-6), 7,01 (d, 1H, J=1,7 Hz, H-4), 3,41 (t, 2H, J=6,7 Hz, CH_{2}Cl), 1,91 (m, 2H, CH_{2}), 1,67 (m, 4H, 2 x CH_{2}), 1,34 (m, 1H), 1,20 (m, 1H), 1,01 (m, 1H), 0,74 (d, 3H, J=6,7 Hz, CH_{3}), 0,66 (d, 3H, J=6,7 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 8.49 (br s, 1H, NH), 7.24 (dt, 1H, J = 1.9 Hz, H-6), 7.01 (d, 1H, J = 1.7 Hz, H-4), 3.41 (t, 2H, J = 6.7 Hz, CH2Cl), 1.91 (m, 2H, CH2), 1.67 (m, 4H, 2 x CH2), 1.34 (m, 1H), 1.20 (m, 1H), 1.01 (m, 1H), 0.74 (d, 3H, J = 6.7 Hz, CH 3), 0.66 (d, 3H, J = 6.7 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 181,0, 137,5, 135,4, 128,2, 127,6, 122,2, 115,4, 54,5, 46,3, 44,3, 39,2, 32,4, 25,3, 24,3, 23,1, 21,1 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 181.0, 137.5, 135.4, 128.2, 127.6, 122.2, 115.4, 54.5, 46.3, 44.3, 39.2, 32.4, 25.3, 24.3, 23.1, 21.1 ppm.
Análisis elemental de la fórmula C_{16}H_{22}ClNO (279,81):Elemental analysis of the formula C 16 H 22 ClNO (279.81):
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Se disolvió 3-(4-clorobutil)-3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona (5,40 g, 20 mmoles) en 40 ml de ácido acético glacial, se introdujeron 3,2 ml (40 mmoles) en cloruro de sulfurilo a temperatura ambiente, y la solución se mantuvo a 60ºC durante 4 horas. A continuación, la mezcla de reacción se enfrió, se vertió en hielo y se extrajo con éter dietílico. La fase éter se extrajo dos veces con 10% en volumen de solución de NaOH, se secó sobre sulfato sódico y se evaporó. El aceite amarillo pálido obtenido de esta manera se trituró con hexano, la sustancia blanca separada en forma cristalina se agitó en hexano, se filtró, se lavó con hexano, se secó y se utilizó para la reacción de acoplamiento sin purificación. Pueden obtenerse muestras analíticas mediante recristalización a partir de la mezcla de hexano y acetato de etilo.It dissolved 3- (4-Chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one (5.40 g, 20 mmol) in 40 ml of glacial acetic acid, se introduced 3.2 ml (40 mmol) in sulfuryl chloride at room temperature, and the solution was maintained at 60 ° C for 4 hours. Then the reaction mixture was cooled, poured into ice and extracted with diethyl ether. The ether phase was extracted two times with 10% by volume NaOH solution, dried over sulfate sodium and evaporated. The pale yellow oil obtained from this way it was triturated with hexane, the white substance separated in form crystalline was stirred in hexane, filtered, washed with hexane, dried and used for the coupling reaction without purification. Analytical samples can be obtained by recrystallization from the mixture of hexane and acetate ethyl.
P.f.: 104ºC a 105ºC (hexano-acetato de etilo).Mp .: 104 ° C to 105 ° C (hexane-ethyl acetate).
IR (KBr): 3184, 1709, 1080, 853 cm^{-1}.IR (KBr): 3184, 1709, 1080, 853 cm -1.
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RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 8,22 (br s, 1H, NH), 6,99 (dd, 1H, J=7,6, 2,3 Hz), 6,81 (dd, 1H, J=7,6, 2,3 Hz), 3,42 (t, 2H, J=6,7 Hz, CH_{2}Cl), 2,00-1,88 (m, 2H, CH_{2}), 1,82-1,60 (m, 4H, 2 x CH_{2}), 1,30-1,16 (m, 1H), 1,12-1,00 (m, 1H), 0,66 (t, 3H, J=7,4 Hz, CH_{3}).1 H NMR (CDCl 3, TMS, 400 MHz): 8.22 (br s, 1H, NH), 6.99 (dd, 1H, J = 7.6, 2.3 Hz), 6.81 (dd, 1H, J = 7.6, 2.3 Hz), 3.42 (t, 2H, J = 6.7 Hz, CH2Cl), 2.00-1.88 (m, 2H, CH2), 1.82-1.60 (m, 4H, 2 x CH2), 1.30-1.16 (m, 1H), 1.12-1.00 (m, 1H), 0.66 (t, 3H, J = 7.4 Hz, CH 3).
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 180,6, 158,8 (d, J=244,5 Hz), 135,1 (d, J=2,3 Hz), 134,9 (d, J=8,4 Hz), 114,8 (d, J=26,3 Hz), 114,8 (d, J=11,0 Hz), 109,7 (d, J=24,4 Hz), 55,8 (d, J=1,9 Hz), 44,3, 36,8, 32,5, 31,1, 21,7, 8,5.NMR - 13 C (CDCl 3, TMS, 101 MHz): 180.6, 158.8 (d, J = 244.5 Hz), 135.1 (d, J = 2.3 Hz), 134.9 (d, J = 8.4 Hz), 114.8 (d, J = 26.3 Hz), 114.8 (d, J = 11.0 Hz), 109.7 (d, J = 24.4 Hz), 55.8 (d, J = 1.9 Hz), 44.3, 36.8, 32.5, 31.1, 21.7, 8.5.
Análisis elemental de la fórmula C_{16}H_{22}ClNO (279,81):Elemental analysis of the formula C 16 H 22 ClNO (279.81):
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Se disolvió 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona (12,59 g, 50 mmoles) en la mezcla de 100 ml de dioxano y 100 ml de agua. Se introdujo una mezcla de 2,84 ml de bromuro (55 mmoles), 11,9 g de KBr (100 mmoles) y 50 ml de agua en la solución a una temperatura de entre 80ºC y 90ºC dentro de un periodo de media hora. La mezcla de reacción se mantuvo a la misma temperatura durante media hora adicional y se dejó enfriar. A continuación, se introdujeron 500 ml de agua en la mezcla. El producto se separó en forma de cristales blancos. La sustancia separada se separó por filtración, se lavó con agua y hexano y se utilizó para la reacción de acoplamiento sin purificación. Pueden obtenerse muestras analíticas mediante recristalización a partir de una mezcla de hexano y acetato de etilo.It dissolved 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one (12.59 g, 50 mmol) in the mixture of 100 ml of dioxane and 100 ml of Water. A mixture of 2.84 ml of bromide (55 mmol) was introduced, 11.9 g of KBr (100 mmol) and 50 ml of water in the solution at a temperature between 80ºC and 90ºC within an average period hour. The reaction mixture was kept at the same temperature. for an additional half hour and allowed to cool. Then it They introduced 500 ml of water into the mixture. The product separated into White crystals form. The separated substance was separated by filtration, washed with water and hexane and used for the reaction coupling without purification. Samples can be obtained analytical by recrystallization from a mixture of hexane and ethyl acetate.
P.f.: 117ºC a 118ºC (hexano-acetato de etilo).Mp .: 117 ° C to 118 ° C (hexane-ethyl acetate).
IR (KBr): 3286, 1717, 1198, 817 cm^{-1}.IR (KBr): 3286, 1717, 1198, 817 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): \delta 9,28 (br s, 1H, NH), 7,35 (dd, 1H, J=8,2, 2,0 Hz, H-6), 7,24 (d, 1H, J=2,0 Hz, H-4), 6,84 (d, 1H, J=8,2 Hz, H-7), 3,41 (t, 2H, J=6,8 Hz, CH_{2}Cl), 1,98-1,75 (m, 2H, CH_{2}), 1,74-1,60 (m, 4H, 2 x CH_{2}), 1,27-1,16 (m, 1H), 1,11-1,01 (m, 1H), 0,64 (t, 3H, J=7,4 Hz, CH_{3}).1 H NMR (CDCl 3, TMS, 400 MHz): δ 9.28 (br s, 1H, NH), 7.35 (dd, 1H, J = 8.2, 2.0 Hz, H-6), 7.24 (d, 1H, J = 2.0 Hz, H-4), 6.84 (d, 1H, J = 8.2 Hz, H-7), 3.41 (t, 2H, J = 6.8 Hz, CH2Cl), 1.98-1.75 (m, 2H, CH2), 1.74-1.60 (m, 4H, 2 x CH2), 1.27-1.16 (m, 1H), 1.11-1.01 (m, 1H), 0.64 (t, 3H, J = 7.4 Hz, CH 3).
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,3, 140,4, 134,6, 130,7, 126,1, 115,3, 111,3, 54,5, 44,3, 36,7, 32,8, 30,9, 21,7, 8,5.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.3, 140.4, 134.6, 130.7, 126.1, 115.3, 111.3, 54.5, 44.3, 36.7, 32.8, 30.9, 21.7, 8.5.
Análisis elemental de la fórmula C_{14}H_{17}BrClNO (330,65):Elemental analysis of the formula C 14 H 17 BrClNO (330.65):
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Se enfriaron hasta 0ºC 90 ml de ácido clorosulfónico y se añadió 3-(4-clorobutil)-3-etil oxindol (11,34 g, 45 mmoles) al mismo en partes de manera que la temperatura no excediese 2ºC. A continuación, se dejó que la solución se calentase hasta la temperatura ambiente bajo agitación, se pipeteó sobre hielo dentro de un periodo de media hora, el precipitado blanco separado se separó mediante filtración, se lavó con agua y hexano y se utilizó para la reacción de acoplamiento sin purificación. Pueden obtenerse muestras analíticas mediante recristalización a partir de una mezcla de hexano y acetato de etilo.90 ml of acid were cooled to 0 ° C chlorosulfonic and was added 3- (4-Chlorobutyl) -3-ethyl oxindole (11.34 g, 45 mmol) therein in parts so that the temperature does not exceed 2 ° C. He then let the solution is heated to room temperature under stirring, was pipetted on ice within a half hour period, the Separated white precipitate was filtered off, washed with water and hexane and was used for the coupling reaction without purification. Analytical samples can be obtained by recrystallization from a mixture of hexane and acetate ethyl.
P.f.: 141ºC a 143ºC.Mp .: 141 ° C to 143 ° C.
IR (KBr): 3197, 1729, 1371, 1176 cm^{-1}.IR (KBr): 3197, 1729, 1371, 1176 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 9,39 (br s, 1H, NH), 7,99 (dd, 1H, J=8,4, 1,9 Hz, H-6), 7,80 (d, 1H, J=1,9 Hz, H-4), 7,16 (d, 1H, J=8,4 Hz, H-7), 3,46-3,41 (m, 2H, CH_{2}Cl), 2,10-1,83 (m, 4H, 2 x CH_{2}), 1,73-1,66 (m, 2H), 1,32-1,18 (m, 1H), 1,14-1,00 (m, 1H), 0,68 (t, 3H, J=7,4 Hz, CH_{3}) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 9.39 (br s, 1H, NH), 7.99 (dd, 1H, J = 8.4, 1.9 Hz, H-6), 7.80 (d, 1H, J = 1.9 Hz, H-4), 7.16 (d, 1H, J = 8.4 Hz, H-7), 3.46-3.41 (m, 2H, CH2Cl), 2.10-1.83 (m, 4H, 2 x CH2), 1.73-1.66 (m, 2H), 1.32-1.18 (m, 1H), 1.14-1.00 (m, 1H), 0.68 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,4, 147,6, 138,4, 133,9, 128,8, 121,9, 110,1, 54,5, 44,2, 36,4, 32,2, 30,9, 21,5, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.4, 147.6, 138.4, 133.9, 128.8, 121.9, 110.1, 54.5, 44.2, 36.4, 32.2, 30.9, 21.5, 8.5 ppm.
Análisis de la fórmula C_{14}H_{17}Cl_{2}NO_{3}S (350,27):Formula Analysis C 14 H 17 Cl 2 NO 3 S (350.27):
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Se disolvió cloruro de 3-(4-clorobutil)-3-etil-2-oxoindolín-5-sulfonilo (9,96 g, 30 mmoles) en 450 ml de etanol y se introdujo una solución de amonio acuoso al 25% (9 ml, 120 mmoles) en la solución a una temperatura de entre 0ºC y 2ºC. A continuación, la mezcla se dejó que se calentase hasta la temperatura ambiente y se agitó adicionalmente durante 1 hora. Después, la solución se evaporó, se agitó en agua la sustancia blanca residual, se filtró, se lavó con agua y hexano, y se utilizó para la reacción de acoplamiento sin purificación.Chloride was dissolved 3- (4-Chlorobutyl) -3-ethyl-2-oxoindolin-5-sulfonyl (9.96 g, 30 mmol) in 450 ml of ethanol and introduced a 25% aqueous ammonium solution (9 ml, 120 mmol) in the solution at a temperature between 0 ° C and 2 ° C. Then, the mixture was allowed to warm to room temperature and It was stirred further for 1 hour. Then the solution is evaporated, the residual white substance was stirred in water, filtered, washed with water and hexane, and used for the reaction of coupling without purification.
Pueden obtenerse muestras analíticas mediante recristalización a partir de acetato de etilo.Analytical samples can be obtained by recrystallization from ethyl acetate.
P.f.: 171ºC a 172ºC (acetato de etilo).Mp .: 171 ° C to 172 ° C (ethyl acetate).
IR (KBr): 3343, 3265, 1725, 1327, 1169 cm^{-1}.IR (KBr): 3343, 3265, 1725, 1327, 1169 cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 10,8 (br s, 1H, NH), 7,70 (dd, 1H, J=8,1, 1,8 Hz, H-6), 7,65 (d, 1H, J=1,7 Hz, H-4), 6,98 (d, 1H, J=8,1 Hz, H-7), 3,54-3,49 (m, 2H, CH_{2}Cl), 1,82-1,73 (m, 4H, 2 x CH_{2}), 1,59 (quinteto, 2H, J=7,2Hz, CH_{2}), 1,15-1,00 (m, 1H), 1,00-0,85 (m, 1H), 0,52 (t, 3H, J=7,4 Hz, CH_{3}) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 10.8 (br s, 1H, NH), 7.70 (dd, 1H, J = 8.1, 1.8 Hz, H-6), 7.65 (d, 1H, J = 1.7 Hz, H-4), 6.98 (d, 1H, J = 8.1 Hz, H-7), 3.54-3.49 (m, 2H, CH2Cl), 1.82-1.73 (m, 4H, 2 x CH2), 1.59 (quintet, 2H, J = 7.2Hz, CH2), 1.15-1.00 (m, 1H), 1.00-0.85 (m, 1H), 0.52 (t, 3H, J = 7.4 Hz, CH 3) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 181,0, 145,7, 137,6, 132,6, 126,5, 120,9, 109,1, 53,4, 45,1, 36,2, 32,3, 30,3, 21,5, 8,5 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 181.0, 145.7, 137.6, 132.6, 126.5, 120.9, 109.1, 53.4, 45.1, 36.2, 32.3, 30.3, 21.5, 8.5 ppm.
Análisis elemental de la fórmula C_{14}H_{19}ClN_{2}O_{3}S (330,84):Elemental analysis of the formula C 14 H 19 ClN 2 O 3 S (330.84):
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En la reacción de acoplamiento, se acopló el compuesto cloroalquilo apropiado con la amina secundaria. Se calentó hasta 180ºC el fundido de la base (12 mmoles) bajo agitación lenta, y el compuesto cloroalquilo (12 mmoles) y el carbonato sódico (1,36 g, 12 mmoles) se añadió a la mezcla a la misma temperatura. La mezcla se hizo reaccionar durante 1 hora, se dejó enfriar, se añadieron acetato de etilo y agua a la mezcla y se separaron las fases. La fase orgánica se evaporó, el aceite residual se sometió a cromatografía utilizando una columna corta y acetato de etilo como eluyente. Los compuestos deseados se prepararon como productos principales.In the coupling reaction, the Appropriate chloroalkyl compound with the secondary amine. Be the base melt (12 mmol) was heated to 180 ° C under stirring slow, and the chloroalkyl compound (12 mmol) and carbonate Sodium (1.36 g, 12 mmol) was added to the mixture thereto temperature. The mixture was reacted for 1 hour, allowed cool, ethyl acetate and water were added to the mixture and They separated the phases. The organic phase evaporated, the residual oil was chromatographed using a short column and acetate of ethyl as eluent. The desired compounds were prepared as main products.
Si el producto purificado mediante cromatografía de columna se torna cristalino tras la trituración del mismo con éter dietílico, se separa mediante filtración y se recristaliza a partir del solvente indicado superado el punto de fusión de la sustancia dada. Se obtuvieron los compuestos deseados en forma de cristales blancos.If the product purified by chromatography column becomes crystalline after crushing it with diethyl ether, filtered off and recrystallized from from the indicated solvent exceeded the melting point of the given substance The desired compounds were obtained in the form of white crystals
Si el producto básico no se torna cristalino tras añadir éter dietílico, se disuelve en 200 ml de éter, se separa por filtración la reducida cantidad de precipitado flotante, y a la solución pura se añade bajo agitación vigorosa una solución de la cantidad calculada (un equivalente molar) de cloruro de hidrógeno en 50 ml de éter dietílico. La sal blanca separada se filtra, se lava con éter y se seca en una pistola de vacío a temperatura ambiente durante 3 horas. Si resulta necesario, la sal hidrocloruro se cristaliza nuevamente.If the commodity does not become crystalline after adding diethyl ether, it is dissolved in 200 ml of ether, filter out the reduced amount of floating precipitate, and to the pure solution a solution is added under vigorous stirring of the calculated amount (a molar equivalent) of chloride of hydrogen in 50 ml of diethyl ether. The separated white salt is filter, wash with ether and dry in a vacuum gun to room temperature for 3 hours. If necessary, salt hydrochloride crystallizes again.
Si el producto básico no cristaliza tras la adición de éter dietílico y no proporciona una sal fácilmente filtrable con cloruro de hidrógeno, se disuelve en 100 ml de acetato de etilo caliente, y se introduce en la mezcla una solución de 1 equivalente molar de ácido oxálico dihidrato en 50 ml de acetato de etilo caliente dentro de un periodo de 10 minutos, bajo agitación. La sal oxalato blanca se separa tras el enfriamiento. Se separa mediante filtración a temperatura ambiente, se lava con acetato de etilo y hexano, y se seca.If the commodity does not crystallize after addition of diethyl ether and does not provide a salt easily filterable with hydrogen chloride, dissolved in 100 ml of hot ethyl acetate, and a solution is introduced into the mixture of 1 molar equivalent of oxalic acid dihydrate in 50 ml of hot ethyl acetate within a period of 10 minutes, under agitation. The white oxalate salt separates after cooling. Be separated by filtration at room temperature, washed with ethyl acetate and hexane, and dried.
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El compuesto del título se preparó según el procedimiento "D" mediante la aplicación del procedimiento de procesado 1 partiendo de 3-(3-cloropropil)-3-etil-1,3-dihidro-2H-indol-2-ona y 2-cloro-6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to procedure "D" by applying the procedure of processed 1 starting from 3- (3-Chloropropyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 2-Chloro-6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 130ºC a 132ºC (hexano-acetato de etilo).Mp .: 130 ° C to 132 ° C (hexane-ethyl acetate).
IR (KBr): 3107, 3059, 1706 (C=O) cm^{-1}.IR (KBr): 3107, 3059, 1706 (C = O) cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,63 (3H, t, J=7,4 Hz), 1,22-1,10 (1H, m), 1,46-1,30 (1H, m), 1,90-1,77 (2H, m), 1,98-1,90 (2H, m), 2,42 (2H, t, J=7,4 Hz), 2,64 (2H, t, J=5,7 Hz), 2,81 (2H, t, J=5,4 Hz), 3,32 (1H, d, J=14,4 Hz), 3,42 (1H, d, J=14,4 Hz), 6,65 (1H, d, J=5,2 Hz), 6,87 (1H, d, J=7,7 Hz), 7,03 (1H, d, J=5,2 Hz), 7,04 (1H, dt, J=1,0, 7,5 Hz), 7,12 (1H, dd, J=0,6, 7,3 Hz), 7,18 (1H, dt, J=1,3, 7,6 Hz), 8,0 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.63 (3H, t, J = 7.4 Hz), 1.22-1.10 (1H, m), 1.46-1.30 (1H, m), 1.90-1.77 (2H, m), 1.98-1.90 (2H, m), 2.42 (2H, t, J = 7.4 Hz), 2.64 (2H, t, J = 5.7 Hz), 2.81 (2H, t, J = 5.4 Hz), 3.32 (1H, d, J = 14.4 Hz), 3.42 (1H, d, J = 14.4 Hz), 6.65 (1H, d, J = 5.2 Hz), 6.87 (1H, d, J = 7.7 Hz), 7.03 (1H, d, J = 5.2 Hz), 7.04 (1H, dt, J = 1.0, 7.5 Hz), 7.12 (1H, dd, J = 0.6, 7.3 Hz), 7.18 (1H, dt, J = 1.3, 7.6 Hz), 8.0 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,5, 141,4, 133,7, 133,3, 132,5, 127,6, 125,2, 123,0, 122,6, 122,3, 109,5, 57,5, 54,0, 52,9, 50,7, 35,3, 31,0, 25,4, 22,1, 8,6 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.5, 141.4, 133.7, 133.3, 132.5, 127.6, 125.2, 123.0, 122.6, 122.3, 109.5, 57.5, 54.0, 52.9, 50.7, 35.3, 31.0, 25.4, 22.1, 8.6 ppm.
Análisis de la fórmula C_{20}H_{24}N_{2}OS (340,49):Analysis of the formula C 20 H 24 N 2 OS (340.49):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 1, partiendo de 5-cloro-3-(3-cloropropil)-3-etil-1,3-dihidro-2H-indol-2-ona y 2-cloro-6,7-dihidro-4H-tieno[3,2-c]-piridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 1, starting from 5-Chloro-3- (3-chloropropyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 2-Chloro-6,7-dihydro-4H-thieno [3,2-c] -pyridine.
P.f.: 66ºC a 69ºC (hexano-acetato de etilo).Mp .: 66 ° C to 69 ° C (hexane-ethyl acetate).
IR (KBr): 1652 (C=O) cm^{-1}.IR (KBr): 1652 (C = O) cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,62 (3H, t, J=7,4 Hz), 1,18-1,14 (1H, m), 1,40-1,36 (1H, m), 1,85-1,74 (2H, m), 1,98-1,90 (2H, m), 2,47-2,40 (2H, m), 2,67 (2H, t, J=5,5 Hz), 2,83 (2H, t, J=5,5 Hz), 3,42 (2H, s), 6,67 (1H, d, J=5,2 Hz), 6,74 (1H, d, J=8,2 Hz), 7,03 (1H, d, J=5,1 Hz), 7,09 (1H, d, J=2,1 Hz), 7,15 (1H, dd, J=2,2, 8,1 Hz), 9,39 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), 1.18-1.14 (1H, m), 1.40-1.36 (1H, m), 1.85-1.74 (2H, m), 1.98-1.90 (2H, m), 2.47-2.40 (2H, m), 2.67 (2H, t, J = 5.5 Hz), 2.83 (2H, t, J = 5.5 Hz), 3.42 (2H, s), 6.67 (1H, d, J = 5.2 Hz), 6.74 (1H, d, J = 8.2 Hz), 7.03 (1H, d, J = 5.1 Hz), 7.09 (1H, d, J = 2.1 Hz), 7.15 (1H, dd, J = 2.2, 8.1 Hz), 9.39 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,2, 140,1, 134,4, 133,6, 133,3, 127,7, 127,7, 125,6, 123,3, 122,6, 110,5, 57,4, 54,5, 52,9, 50,8, 35,1, 31,0, 25,3, 22,1, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.2, 140.1, 134.4, 133.6, 133.3, 127.7, 127.7, 125.6, 123.3, 122.6, 110.5, 57.4, 54.5, 52.9, 50.8, 35.1, 31.0, 25.3, 22.1, 8.5 ppm.
Análisis elemental de la fórmula C_{20}H_{23}ClN_{2}OS (374,94):Elemental analysis of the formula C 20 H 23 ClN 2 OS (374.94):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 3, partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 4-(3-trifluorometilfenil)-1,2,3,6-tetrahidropiridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 3, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 4- (3-Trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine.
P.f.: 136ºC a 139ºC.Mp .: 136 ° C to 139 ° C.
IR (KBr): 3185, 1707 (C=O) cm^{-1}IR (KBr): 3185, 1707 (C = O) cm -1
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 10,4 (1H, s), 7,77 (1H, d), 7,75 (1H, s), 7,67 (1H, d, J=7,7 Hz), 7,61 (1H, t, J=7,7 Hz), 6,30 (1H, s), 5,2 (4H, br s), 3,69 (2H, s), 3,22 (2H, s), 2,90 (2H, t, J=8,0 Hz), 2,73 (2H, s), 1,80-1,66 (4H, m), 1,62-1,48 (2H, m), 1,06-0,94 (1H, m), 0,88-0,76 (1H, m), 0,51 (3H, t, J=7,4 Hz) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 10.4 (1H, s), 7.77 (1H, d), 7.75 (1H, s), 7.67 (1H, d, J = 7.7 Hz), 7.61 (1H, t, J = 7.7 Hz), 6.30 (1H, s), 5.2 (4H, br s), 3.69 (2H, s), 3.22 (2H, s), 2.90 (2H, t, J = 8.0 Hz), 2.73 (2H, s), 1.80-1.66 (4H, m), 1.62-1.48 (2H, m), 1.06-0.94 (1H, m), 0.88-0.76 (1H, m), 0.51 (3H, t, J = 7.4 Hz) ppm.
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RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 180,9, 164,6, 142,7, 139,9, 139,1, 132,2, 129,9, 129,6 (q, J=31,7 Hz), 129,1, 127,8, 124,5 (q, J=3,8 Hz), 124,4 (q, J=272,4 Hz), 123,2, 121,7, 121,5 (q, J=3,8 Hz), 110,4, 109,4, 54,8, 53,2, 49,9, 48,2, 36,7, 30,4, 24,1, 24,0, 21,6, 8,6 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 180.9, 164.6, 142.7, 139.9, 139.1, 132.2, 129.9, 129.6 (q, J = 31.7 Hz), 129.1, 127.8, 124.5 (q, J = 3.8 Hz), 124.4 (q, J = 272.4 Hz), 123.2, 121.7, 121.5 (q, J = 3.8 Hz), 110.4, 109.4, 54.8, 53.2, 49.9, 48.2, 36.7, 30.4, 24.1, 24.0, 21.6, 8.6 ppm.
Análisis elemental de la fórmula C_{28}H_{31}F_{3}N_{2}O_{5} (532,56):Elemental analysis of the formula C 28 H 31 F 3 N 2 O 5 (532.56):
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El compuesto del título se preparó según el procedimiento D, mediante la aplicación del procedimiento de procesado 1, partiendo de 5-cloro-3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to procedure D, by applying the procedure of processed 1, starting from 5-chloro-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 213ºC a 215ºC.Mp .: 213 ° C to 215 ° C.
IR (KBr): 3186, 2473, 1708 (C=O) cm^{-1}.IR (KBr): 3186, 2473, 1708 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,51 (3H, t, J=7,4 Hz), 0,90-0,75 (1H, m), 1,02-0,90 (1H, m), 1,87-1,69 (6H, m), 3,05 (4H, br s), 3,26 (1H, br s), 3,36 (1H, br s), 4,09 (1H, br s), 4,34 (1H, br s), 6,88 (1H, d, J=8,1 Hz), 6,88 (1H, d, J=5,2 Hz), 7,23 (1H, dd, J=2,1, 8,2 Hz), 7,36 (1H, d, J=2,0 Hz), 7,45 (1H, d, J=5,2 Hz), 10,6 (1H, s), 11,1 (1H, br s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.90-0.75 (1H, m), 1.02-0.90 (1H, m), 1.87-1.69 (6H, m), 3.05 (4H, br s), 3.26 (1H, br s), 3.36 (1H, br s), 4.09 (1H, br s), 4.34 (1H, br s), 6.88 (1H, d, J = 8.1 Hz), 6.88 (1H, d, J = 5.2 Hz), 7.23 (1H, dd, J = 2.1, 8.2 Hz), 7.36 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 5.2 Hz), 10.6 (1H, s), 11.1 (1H, br s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 180,4, 141,6, 134,4, 131,6, 128,3, 127,7, 125,9, 125,3, 125,2, 123,5, 110,7, 54,6, 53,8, 50,0, 49,1, 36,4, 30,2, 23,6, 21,7, 21,4, 8,5 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 180.4, 141.6, 134.4, 131.6, 128.3, 127.7, 125.9, 125.3, 125.2, 123.5, 110.7, 54.6, 53.8, 50.0, 49.1, 36.4, 30.2, 23.6, 21.7, 21.4, 8.5 ppm.
Análisis elemental de la fórmula C_{21}H_{26}Cl_{2}NO_{2}S (425,42):Elemental analysis of the formula C 21 H 26 Cl 2 NO 2 S (425.42):
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El compuesto del título se preparó según el procedimiento D, mediante la aplicación del procedimiento de procesado 1, partiendo de 5-bromo-3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to procedure D, by applying the procedure of processed 1, starting from 5-Bromo-3- (4-chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 149ºC a 151ºC (hexano-acetato de etilo).Mp .: 149 ° C to 151 ° C (hexane-ethyl acetate).
IR (KBr): 3444, 3110, 1720 (C=O) cm^{-1}.IR (KBr): 3444, 3110, 1720 (C = O) cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,62 (3H, t, J=7,4 Hz), 0,98-0,86 (1H, m), 1,18-1,04 (1H, m), 1,52-1,45 (2H, m), 1,80-0,71 (2H, m), 1,97-1,88 (2H, m), 2,41 (2H, t, J=7,6 Hz), 2,71 (2H, t, J=5,6 Hz), 2,83 (2H, t, J=5,6 Hz), 3,47 (2H, s), 6,72 (1H, d, J=8,2 Hz), 6,68 (1H, d, J=5,1 Hz), 7,04 (1H, d, J=5,1 Hz), 7,22 (1H, d, J=2,0 Hz), 7,30 (1H, dd, J=2,0, 8,2 Hz), 9,34 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.62 (3H, t, J = 7.4 Hz), 0.98-0.86 (1H, m), 1.18-1.04 (1H, m), 1.52-1.45 (2H, m), 1.80-0.71 (2H, m), 1.97-1.88 (2H, m), 2.41 (2H, t, J = 7.6 Hz), 2.71 (2H, t, J = 5.6 Hz), 2.83 (2H, t, J = 5.6 Hz), 3.47 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 6.68 (1H, d, J = 5.1 Hz), 7.04 (1H, d, J = 5.1 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 2.0, 8.2 Hz), 9.34 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,3, 140,6, 134,9, 133,7, 133,3, 130,5, 126,1, 125,2, 122,6, 115,0, 111,1, 57,3, 54,6, 52,9, 50,7, 37,5, 37,5, 31,0, 25,3, 22,2, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.3, 140.6, 134.9, 133.7, 133.3, 130.5, 126.1, 125.2, 122.6, 115.0, 111.1, 57.3, 54.6, 52.9, 50.7, 37.5, 37.5, 31.0, 25.3, 22.2, 8.5 ppm.
Análisis elemental de la fórmula C_{16}H_{22}ClNO (279,81):Elemental analysis of the formula C 16 H 22 ClNO (279.81):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 1, partiendo de 3-(4-clorobutil)-3-isobutil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 1, starting from 3- (4-Chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 114ºC a 116ºC (hexano-acetato de etilo).Mp .: 114 ° C to 116 ° C (hexane-ethyl acetate).
IR (KBr): 3201, 1718 (C=O) cm^{-1}.IR (KBr): 3201, 1718 (C = O) cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,60 (3H, d, J=6,7 Hz), 0,72 (3H, d, J=6,7 Hz), 0,90-0,86 (1H, m), 1,16-1,04 (1H, m), 1,38-1,25 (1H, m), 1,48-1,40 (2H, m), 1,80-1,68 (2H, m), 1,94-1,88 (2H, m), 2,37 (2H, t, J=7,8 Hz), 2,68 (2H, t, J=5,7 Hz), 2,81 (2H, t, J=5,5 Hz), 3,45 (2H, s), 6,67 (1H, d, J=5,1 Hz), 6,89 (1H, d, J=7,7 Hz), 7,02 (1H, dt, J=0,9, 7,5 Hz), 7,03 (1H, d, J=5,1 Hz), 7,10 (1H, d, J=6,8 Hz), 7,18 (1H, dt, J=1,2, 7,7 Hz), 9,06 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.60 (3H, d, J = 6.7 Hz), 0.72 (3H, d, J = 6.7 Hz), 0.90-0.86 (1H, m), 1.16-1.04 (1H, m), 1.38-1.25 (1H, m), 1.48-1.40 (2H, m), 1.80-1.68 (2H, m), 1.94-1.88 (2H, m), 2.37 (2H, t, J = 7.8 Hz), 2.68 (2H, t, J = 5.7 Hz), 2.81 (2H, t, J = 5.5 Hz), 3.45 (2H, s), 6.67 (1H, d, J = 5.1 Hz), 6.89 (1H, d, J = 7.7 Hz), 7.02 (1H, dt, J = 0.9, 7.5 Hz), 7.03 (1H, d, J = 5.1 Hz), 7.10 (1H, d, J = 6.8 Hz), 7.18 (1H, dt, J = 1.2, 7.7 Hz), 9.06 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 183,2, 141,2, 133,7, 133,3, 132,9, 127,5, 125,2, 123,3, 122,5, 122,2, 109,6, 57,4, 53,1, 53,0, 50,0, 46,3, 40,0, 27,4, 25,3, 24,2, 23,1, 21,7, 21,7 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 183.2, 141.2, 133.7, 133.3, 132.9, 127.5, 125.2, 123.3, 122.5, 122.2, 109.6, 57.4, 53.1, 53.0, 50.0, 46.3, 40.0, 27.4, 25.3, 24.2, 23.1, 21.7, 21.7 ppm.
Análisis elemental de la fórmula C_{23}H_{30}N_{2}OS (382,57):Elemental analysis of the formula C 23 H 30 N 2 OS (382.57):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 2, partiendo de 3-(4-clorobutil)-3-isobutil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 2, starting from 3- (4-Chlorobutyl) -3-isobutyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 143ºC a 144ºC.Mp .: 143 ° C to 144 ° C.
IR (KBr): 3427, 1706 (C=O) cm^{-1}.IR (KBr): 3427, 1706 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 11,2 (1H, br s), 10,5 (1H, s), 7,48 (1H, d, J=5,1 Hz), 7,25 (1H, d, J=7,2 Hz), 7,21 (1H, dt, J=1,2, 7,6 Hz), 7,03 (1H, dt, J=1,0, 7,5 Hz), 6,91 (1H, d, J=5,3 Hz), 6,90 (1H, d, J=7,8 Hz), 4,37 (1H, br s), 4,11 (1H, br s), 3,63 (1H, br s), 3,25 (1H, br s), 3,20 (1H, br s), 3,07 (3H, br s), 1,83-1,72 (6H, m), 1,01 (1H, br s), 0,85 (1H, br s), 0,54 (3H, t, J=7,4 Hz) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 11.2 (1H, br s), 10.5 (1H, s), 7.48 (1H, d, J = 5.1 Hz), 7.25 (1H, d, J = 7.2 Hz), 7.21 (1H, dt, J = 1.2, 7.6 Hz), 7.03 (1H, dt, J = 1.0, 7.5 Hz), 6.91 (1H, d, J = 5.3 Hz), 6.90 (1H, d, J = 7.8 Hz), 4.37 (1H, br s), 4.11 (1H, br s), 3.63 (1H, br s), 3.25 (1H, br s), 3.20 (1H, br s), 3.07 (3H, br s), 1.83-1.72 (6H, m), 1.01 (1H, br s), 0.85 (1H, br s), 0.54 (3H, t, J = 7.4 Hz) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 50 MHz): 180,7, 142,7, 132,1, 131,5, 128,2, 127,7, 125,3, 123,2, 121,6, 109,3, 54,6, 53,1, 49,9, 49,0, 36,5, 30,3, 23,6, 21,7, 21,4, 8,5 ppm.NMR - 13 C (DMSO-d6, TMS, 50 MHz): 180.7, 142.7, 132.1, 131.5, 128.2, 127.7, 125.3, 123.2, 121.6, 109.3, 54.6, 53.1, 49.9, 49.0, 36.5, 30.3, 23.6, 21.7, 21.4, 8.5 ppm.
Análisis elemental de la fórmula C_{21}H_{27}ClN_{2}OS (390,98):Elemental analysis of the formula C 21 H 27 ClN 2 OS (390.98):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 1, partiendo de 3-(4-clorobutil)-3-etil-5-metil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 1, starting from 3- (4-Chlorobutyl) -3-ethyl-5-methyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 138-140ºC (hexano-acetato de etilo)Mp .: 138-140 ° C (hexane-ethyl acetate)
IR (KBr): 3239, 1710 (C=O), 1493 cm^{-1}.IR (KBr): 3239, 1710 (C = O), 1493 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 7,90 (1H, br s), 7,02 (1H, d, J=5,1 Hz), 6,97 (1H, m), 6,90 (1H, m), 6,73 (1H, d, J=7,8 Hz), 6,66 (1H, d, J=5,1 Hz), 3,40 (2H, s), 2,81 (2H, t, J=5,5 Hz), 2,68 (2H, t, J=5,7 Hz), 2,38 (2H, t, J=7,6 Hz), 2,32 (3H, s), 1,88 (2H, m), 1,75 (2H, m), 1,45 (2H, m), 1,10 (1H, m), 0,91 (1H, m), 0,61 (3H, t, J=7,4 Hz) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 7.90 (1H, br s), 7.02 (1H, d, J = 5.1 Hz), 6.97 (1H, m), 6.90 (1H, m), 6.73 (1H, d, J = 7.8 Hz), 6.66 (1H, d, J = 5.1 Hz), 3.40 (2H, s), 2.81 (2H, t, J = 5.5 Hz), 2.68 (2H, t, J = 5.7 Hz), 2.38 (2H, t, J = 7.6 Hz), 2.32 (3H, s), 1.88 (2H, m), 1.75 (2H, m), 1.45 (2H, m), 1.10 (1H, m), 0.91 (1H, m), 0.61 (3H, t, J = 7.4 Hz) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,31, 138,77, 133,79, 133,33, 132,64, 131,77, 127,88, 125,19, 123,78, 122,54, 109,08, 57,50, 54,18, 53,01, 50,79, 37,67, 31,10, 27,50, 25,35, 22,33, 21,21, 8,56 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.31, 138.77, 133.79, 133.33, 132.64, 131.77, 127.88, 125.19, 123.78, 122.54, 109.08, 57.50, 54.18, 53.01, 50.79, 37.67, 31.10, 27.50, 25.35, 22.33, 21.21, 8.56 ppm.
Análisis elemental de la fórmula C_{22}H_{28}N_{2}OS (368,55):Elemental analysis of the formula C 22 H 28 N 2 OS (368.55):
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El compuesto del título se preparó según el procedimiento "D", mediante la aplicación del procedimiento de procesado 1, partiendo de 3-(4-clorobutil)-3-etil-6-fluoro-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina.The title compound was prepared according to "D" procedure, by applying the procedure of processed 1, starting from 3- (4-Chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine.
P.f.: 167ºC a 168ºC.Mp .: 167 ° C to 168 ° C.
IR (KBr): 1707 (C=O), 1140 cm^{-1}.IR (KBr): 1707 (C = O), 1140 cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,50 (3H, t, J=7,3 Hz), 0,85-0,78 (1H, m), 0,99-0,85 (1H, m), 1,57-1,50 (2H, m), 1,79-1,67 (2H, m), 2,86 (2H, t, J=7,4 Hz), 2,97 (2H, s), 3,2 (2H, s), 3,99 (2H, s), 5,0-4,2 (2H, br s), 6,66 (1H, dd, J=2,3, 9,3 Hz), 6,78 (1H, dt, J=2,3, 7,8 Hz), 6,84 (1H, d, J=5,2 Hz), 7,2 (1H, dd, J=5,7, 8,1 Hz), 7,40 (1H, d, J=5,2 Hz), 10,5 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.50 (3H, t, J = 7.3 Hz), 0.85-0.78 (1H, m), 0.99-0.85 (1H, m), 1.57-1.50 (2H, m), 1.79-1.67 (2H, m), 2.86 (2H, t, J = 7.4 Hz), 2.97 (2H, s), 3.2 (2H, s), 3.99 (2H, s), 5.0-4.2 (2H, br s), 6.66 (1H, dd, J = 2.3, 9.3 Hz), 6.78 (1H, dt, J = 2.3, 7.8 Hz), 6.84 (1H, d, J = 5.2 Hz), 7.2 (1H, dd, J = 5.7, 8.1 Hz), 7.40 (1H, d, J = 5.2 Hz), 10.5 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 50 MHz): 8,3, 21,4, 22,5, 24,5, 30,2, 36,5, 49,4, 50,8, 52,8, 55,1, 97,5 (d, J=27,1 Hz), 107,5 (d, J=22,5 Hz), 124,34 (d, J=10,7 Hz), 124,6, 125,3, 127,8, 129,8, 131,8, 144,0 (d, J=12,2 Hz), 161,9 (d, J=240,7 Hz), 163,9, 181,0 ppm.NMR - 13 C (DMSO-d6, TMS, 50 MHz): 8.3, 21.4, 22.5, 24.5, 30.2, 36.5, 49.4, 50.8, 52.8, 55.1, 97.5 (d, J = 27.1 Hz), 107.5 (d, J = 22.5 Hz), 124.34 (d, J = 10.7 Hz), 124.6, 125.3, 127.8, 129.8, 131.8, 144.0 (d, J = 12.2 Hz), 161.9 (d, J = 240.7 Hz), 163.9, 181.0 ppm.
Análisis elemental de la fórmula C_{23}H_{27}FN_{2}O_{5}S (462,54):Elemental analysis of the formula C 23 H 27 FN 2 O 5 S (462.54):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 2.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine. The product was isolated from the reaction mixture by application of the processing procedure 2.
P.f.: 119ºC a 121ºC.Mp .: 119 ° C to 121 ° C.
IR (KBr): 3441, 1712 (C=O), 1184 cm^{-1}.IR (KBr): 3441, 1712 (C = O), 1184 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,60 (1H, t, J=7,4 Hz), 1,00-0,86 (1H, m), 1,16-1,04 (1H, m), 1,95-1,66 (6H, m), 3,20-2,94 (2H, m), 3,22 (2H, br s), 3,50 (2H, br s), 4,33 (2H, br s), 6,78 (1H, d, J=5,2 Hz), 6,81 (1H, dd, J=2,5, 8,1 Hz), 6,87 (1H, dt, J=2,5, 9,1 Hz), 6,95 (1H, dd, J=4,5, 8,5 Hz), 7,21 (1H, d, J=5,1 Hz), 9,74 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.60 (1H, t, J = 7.4 Hz), 1.00-0.86 (1H, m), 1.16-1.04 (1H, m), 1.95-1.66 (6H, m), 3.20-2.94 (2H, m), 3.22 (2H, br s), 3.50 (2H, br s), 4.33 (2H, br s), 6.78 (1H, d, J = 5.2 Hz), 6.81 (1H, dd, J = 2.5, 8.1 Hz), 6.87 (1H, dt, J = 2.5, 9.1 Hz), 6.95 (1H, dd, J = 4.5, 8.5 Hz), 7.21 (1H, d, J = 5.1 Hz), 9.74 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 8,4, 21,1, 21,6, 24,0, 30,9, 36,6, 49,2, 50,3, 54,2, 54,3 (d, J=1,9 Hz), 110,5 (d, J=24,4 Hz), 110,7 (d, J=8,0 Hz), 114,1 (d, J=23,7 Hz), 124,7, 125,4, 126,3, 131,0, 133,5 (d, J=7,6 Hz), 137,7, 159,0 (d, J=239,9 Hz), 181,7 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 8.4, 21.1, 21.6, 24.0, 30.9, 36.6, 49.2, 50.3, 54.2, 54.3 (d, J = 1.9 Hz), 110.5 (d, J = 24.4 Hz), 110.7 (d, J = 8.0 Hz), 114.1 (d, J = 23.7 Hz), 124.7, 125.4, 126.3, 131.0, 133.5 (d, J = 7.6 Hz), 137.7, 159.0 (d, J = 239.9 Hz), 181.7 ppm.
Análisis elemental de la fórmula C_{21}H_{26}ClFN_{2}OS (408,97):Elemental analysis of the formula C 21 H 26 ClFN 2 OS (408.97):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 7-cloro-3-(4-clorobutil)-3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]-piridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 1.The title compound was prepared according to "D" procedure, starting from 7-Chloro-3- (4-chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] -pyridine. The product was isolated from the reaction mixture by application of the processing procedure 1.
P.f.: 194ºC a 196ºC (etanol).Mp .: 194 ° C to 196 ° C (ethanol).
IR (KBr): 1726 (C=O) cm^{-1}IR (KBr): 1726 (C = O) cm -1
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RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,51 (3H, t, J=7,4 Hz), 0,90-0,70 (1H, m), 1,08-0,90 (1H, m), 1,39-1,32 (2H, m), 1,82-1,70 (4H, m), 2,59 (2H, t, J=5,6 Hz), 2,71 (2H, t, J=5,2 Hz), 3,34 (2H, m), 6,74 (1H, d, J=5,1 Hz), 7,25-7,22 (3H, m), 10,84 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.90-0.70 (1H, m), 1.08-0.90 (1H, m), 1.39-1.32 (2H, m), 1.82-1.70 (4H, m), 2.59 (2H, t, J = 5.6 Hz), 2.71 (2H, t, J = 5.2 Hz), 3.34 (2H, m), 6.74 (1H, d, J = 5.1 Hz), 7.25-7.22 (3H, m), 10.84 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 8,5, 22,0, 25,1, 26,9, 30,5, 37,0, 50,5, 52,6, 55,2 (d, J=1,9 Hz), 56,8, 110,4, (d, J=24,0 Hz), 113,4 (d, J=11,1 Hz), 114,6 (d, J=26,7 Hz), 123,0, 125,6, 132,9, 134,3, 135,8 (d, J=8,8 Hz), 136,8 (d, J=2,3 Hz), 158,0 (d, J=240,3 Hz), 180,7 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 8.5, 22.0, 25.1, 26.9, 30.5, 37.0, 50.5, 52.6, 55.2 (d, J = 1.9 Hz), 56.8, 110.4, (d, J = 24.0 Hz), 113.4 (d, J = 11.1 Hz), 114.6 (d, J = 26.7 Hz), 123.0, 125.6, 132.9, 134.3, 135.8 (d, J = 8.8 Hz), 136.8 (d, J = 2.3 Hz), 158.0 (d, J = 240.3 Hz), 180.7 ppm.
Análisis elemental de la fórmula C_{21}H_{24}ClFN_{2}OS (406,95):Elemental analysis of the formula C 21 H 24 ClFN 2 OS (406.95):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 2-cloro-6,7-dihidro-4H-tieno[3,2-c]piridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 1.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 2-Chloro-6,7-dihydro-4H-thieno [3,2-c] pyridine. The product was isolated from the reaction mixture by application of the processing procedure 1.
P.f.: 117ºC a 119ºC (hexano-acetato de etilo).Mp .: 117 ° C to 119 ° C (hexane-ethyl acetate).
IR (KBr): 3299, 1705 (C=O), 769 cm^{-1}.IR (KBr): 3299, 1705 (C = O), 769 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz), 0,62 (3H, t, J=7,4 Hz), 0,95-0,89 (1H, m), 1,18-1,08 (1H, m), 1,51-1,39 (2H, m), 1,84-1,74 (2H, m), 1,97-1,87 (2H, m), 2,36 (2H, t, J=7,8 Hz), 2,70-2,64 (4H, m), 3,34 (2H, s), 0,49 (1H, s), 6,89 (1H, d, J=7,8 Hz), 7,06 (1H, dt, J=1,0, 7,5 Hz), 7,10 (1H, d, J=6,4 Hz), 7,20 (1H, dt, J=1,3, 7,6 Hz), 8,81 (1H, br s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz), 0.62 (3H, t, J = 7.4 Hz), 0.95-0.89 (1H, m), 1.18-1.08 (1H, m), 1.51-1.39 (2H, m), 1.84-1.74 (2H, m), 1.97-1.87 (2H, m), 2.36 (2H, t, J = 7.8 Hz), 2.70-2.64 (4H, m), 3.34 (2H, s), 0.49 (1H, s), 6.89 (1H, d, J = 7.8 Hz), 7.06 (1H, dt, J = 1.0, 7.5 Hz), 7.10 (1H, d, J = 6.4 Hz), 7.20 (1H, dt, J = 1.3, 7.6 Hz), 8.81 (1H, br s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz), 182,6, 141,4, 133,1, 132,5, 132,1, 127,6, 127,0, 124,2, 123,0, 122,3, 109,5, 57,3, 54,2, 52,5, 50,4, 37,5, 31,0, 27,3, 25,1, 22,2, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz), 182.6, 141.4, 133.1, 132.5, 132.1, 127.6, 127.0, 124.2, 123.0, 122.3, 109.5, 57.3, 54.2, 52.5, 50.4, 37.5, 31.0, 27.3, 25.1, 22.2, 8.5 ppm.
Análisis elemental de la fórmula C_{21}H_{25}ClN_{2}OS (388,96):Elemental analysis of the formula C 21 H 25 ClN 2 OS (388.96):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 5-cloro-3-(4-clorobutil)-3-etil-6-fluoro-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]-piridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 1.The title compound was prepared according to "D" procedure, starting from 5-Chloro-3- (4-chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] -pyridine. The product was isolated from the reaction mixture by application of the processing procedure 1.
P.f.: 155ºC a 157ºC (etanol).Mp .: 155 ° C to 157 ° C (ethanol).
IR (KBr): 3112, 1722 (C=O), 1160, 727 cm^{-1}.IR (KBr): 3112, 1722 (C = O), 1160, 727 cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz), 0,63 (3H, t, J=7,4 Hz), 0,96-0,90 (1H, m), 1,18-1,05 (1H, m), 1,55-1,43 (2H, m), 1,80-1,70 (2H, m), 1,96-1,86 (2H, m), 2,42 (2H, t, J=7,7 Hz), 2,72 (2H, t, J=5,2 Hz), 2,83 (2H, t, J=5,3 Hz), 3,48 (2H, s), 6,67 (1H, d, J=8,8 Hz), 6,69 (1H, J=5,1 Hz), 7,05 (1H, J=5,1 Hz), 7,10 (1H, d, J=7,1 Hz), 8,88 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz), 0.63 (3H, t, J = 7.4 Hz), 0.96-0.90 (1H, m), 1.18-1.05 (1H, m), 1.55-1.43 (2H, m), 1.80-1.70 (2H, m), 1.96-1.86 (2H, m), 2.42 (2H, t, J = 7.7 Hz), 2.72 (2H, t, J = 5.2 Hz), 2.83 (2H, t, J = 5.3 Hz), 3.48 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 6.69 (1H, J = 5.1 Hz), 7.05 (1H, J = 5.1 Hz), 7.10 (1H, d, J = 7.1 Hz), 8.88 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 8,5, 22,2, 25,3, 27,4, 31,1, 37,6, 50,8, 53,0, 54,2, 57,3, 99,2 (d, J=26,7 Hz), 114,1 (d, J=18,7 Hz), 122,7, 124,8, 125,2, 129,0 (d, J=3,8 Hz), 133,3, 133,7, 141,0 (d, J=10,7 Hz), 157,5 (d, J=247,2 Hz), 182,1 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 8.5, 22.2, 25.3, 27.4, 31.1, 37.6, 50.8, 53.0, 54.2, 57.3, 99.2 (d, J = 26.7 Hz), 114.1 (d, J = 18.7 Hz), 122.7, 124.8, 125.2, 129.0 (d, J = 3.8 Hz), 133.3, 133.7, 141.0 (d, J = 10.7 Hz), 157.5 (d, J = 247.2 Hz), 182.1 ppm.
Análisis elemental de la fórmula C_{21}H_{24}ClFN_{2}OS (406,95):Elemental analysis of the formula C 21 H 24 ClFN 2 OS (406.95):
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El compuesto del título se preparó según el procedimiento "D", partiendo de 3-(5-bromopentil)-3-etil-1,3-dihidro-2H-indol-2-ona y 6,7-dihidro-4H-tieno[3,2-c]piridina. El producto se aisló a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 3.The title compound was prepared according to "D" procedure, starting from 3- (5-bromopentyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 6,7-dihydro-4H-thieno [3,2-c] pyridine. The product was isolated from the reaction mixture by application of the processing procedure 3.
P.f.: 193ºC a 195ºC.Mp .: 193 ° C to 195 ° C.
IR (KBr): 3200-3100, 1763, 1710 cm^{-1}.IR (KBr): 3200-3100, 1763, 1710 cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,50 (3H, t, J=7,4 Hz), 0,83-0,78 (1H, m), 1,00-0,95 (1H, m), 1,20-1,12 (2H, m), 1,69-1,52 (4H, m), 2,95 (2H, t, J=8,1 Hz), 3,03 (2H, t, J=5,6 Hz), 3,36 (2H, t, J=5,7 Hz), 4,14 (2H, s), 6,85 (1H, d, J=7,5 Hz), 6,86 (1H, d, J=5,2 Hz), 6,98 (1H, dt, J=0,9, 7,5 Hz), 7,16 (1H, dt, J=1,2, 7,7 Hz), 7,19 (1H, d, J=7,3 Hz), 9,4-8,4 (2H, br s), 10,37 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.83-0.78 (1H, m), 1.00-0.95 (1H, m), 1.20-1.12 (2H, m), 1.69-1.52 (4H, m), 2.95 (2H, t, J = 8.1 Hz), 3.03 (2H, t, J = 5.6 Hz), 3.36 (2H, t, J = 5.7 Hz), 4.14 (2H, s), 6.85 (1H, d, J = 7.5 Hz), 6.86 (1H, d, J = 5.2 Hz), 6.98 (1H, dt, J = 0.9, 7.5 Hz), 7.16 (1H, dt, J = 1.2, 7.7 Hz), 7.19 (1H, d, J = 7.3 Hz), 9.4-8.4 (2H, br s), 10.37 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 180,9, 164,4, 142,7, 132,4, 131,7, 129,2, 127,7, 125,4, 125,0, 123,1, 121,6, 109,3, 55,0, 53,2, 50,5, 49,3, 36,9, 30,5, 26,3, 23,8, 23,8, 22,2, 8,6 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 180.9, 164.4, 142.7, 132.4, 131.7, 129.2, 127.7, 125.4, 125.0, 123.1, 121.6, 109.3, 55.0, 53.2, 50.5, 49.3, 36.9, 30.5, 26.3, 23.8, 23.8, 22.2, 8.6 ppm.
Análisis elemental de la fórmula C_{24}H_{30}N_{2}O_{5}S (458,58):Elemental analysis of the formula C 24 H 30 N 2 O 5 S (458.58):
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El compuesto del título se preparó según el procedimiento "D", partiendo de 3-(5-bromopentil)-3-etil-1,3-dihidro-2H-indol-2-ona y 2-cloro-6,7-dihidro-4H-tieno[3,2-c]piridina. Se aisló el producto mediante la aplicación del procedimiento de procesado 2.The title compound was prepared according to "D" procedure, starting from 3- (5-bromopentyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 2-Chloro-6,7-dihydro-4H-thieno [3,2-c] pyridine. The product was isolated by applying the procedure of processed 2.
P.f.: 96ºC a 98ºC.Mp .: 96 ° C to 98 ° C.
IR (KBr): 3426, 2549, 1708 (C=O) cm^{-1}.IR (KBr): 3426, 2549, 1708 (C = O) cm -1.
RMN-^{1}H (CDCl_{3}, TMS, 400 MHz): 0,61 (3H, t, J=7,4 Hz), 0,96-0,86 (1H, m), 1,10-1,04 (1H, m), 1,29-1,20 (2H, m), 1,90-1,70 (6H, m), 3,10 (2H, t, J=8,2 Hz), 3,6-3,2 (4H, br s), 4,5-3,8 (2H, br s), 6,62 (2H, s), 6,95 (1H, d, J=7,7 Hz), 7,03 (1H, dt, J=0,9, 7,4 Hz), 7,09 (1H, d, J=6,4 Hz), 7,19 (1H, dt, J=1,4, 7,5 Hz), 8,94 (1H, s) ppm.1 H NMR (CDCl 3, TMS, 400 MHz): 0.61 (3H, t, J = 7.4 Hz), 0.96-0.86 (1H, m), 1.10-1.04 (1H, m), 1.29-1.20 (2H, m), 1.90-1.70 (6H, m), 3.10 (2H, t, J = 8.2 Hz), 3.6-3.2 (4H, br s), 4.5-3.8 (2H, br s), 6.62 (2H, s), 6.95 (1H, d, J = 7.7 Hz), 7.03 (1H, dt, J = 0.9, 7.4 Hz), 7.09 (1H, d, J = 6.4 Hz), 7.19 (1H, dt, J = 1.4, 7.5 Hz), 8.94 (1H, s) ppm.
RMN-^{13}C (CDCl_{3}, TMS, 101 MHz): 182,2, 141,4, 132,2, 130,3, 129,9, 127,7, 125,8, 123,7, 122,9, 122,4, 109,8, 54,9, 54,0, 49,8, 49,0, 37,0, 31,1, 26,6, 23,7, 23,6, 21,2, 8,5 ppm.NMR - 13 C (CDCl 3, TMS, 101 MHz): 182.2, 141.4, 132.2, 130.3, 129.9, 127.7, 125.8, 123.7, 122.9, 122.4, 109.8, 54.9, 54.0, 49.8, 49.0, 37.0, 31.1, 26.6, 23.7, 23.6, 21.2, 8.5 ppm.
Análisis elemental de la fórmula C_{22}H_{28}Cl_{2}N_{2}OS (439,45):Elemental analysis of the formula C 22 H 28 Cl 2 N 2 OS (439.45):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 3,4-dihidro-1H-isoquinolina. Se aisló el producto a partir de la mezcla de reacción medinate la aplicación del procedimiento de procesado 2.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 3,4-dihydro-1H-isoquinoline. The product was isolated from the reaction mixture medinate the application of the processing procedure 2.
P.f.: 113ºC a 115ºC.Mp .: 113 ° C to 115 ° C.
IR (KBr): 3420, 2875, 1709 (C=O) cm^{-1}.IR (KBr): 3420, 2875, 1709 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,47 (3H, t, J=7,3 Hz), 0,83-0,80 (1H, m), 1,00-0,95 (1H, m), 1,76-1,65 (6H, m), 2,98-2,89 (3H, m), 3,18-3,15 (2H, m), 3,54 (1H, br s), 4,10 (1H, m), 4,15 (1H, d, J=4,7 Hz), 6,83 (1H, d, J=7,6 Hz), 6,96 (1H, dt, J=0,9, 7,5 Hz), 7,24-7,12 (6H, m), 10,4 (1H, s), 11,1 (1H, br s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.47 (3H, t, J = 7.3 Hz), 0.83-0.80 (1H, m), 1.00-0.95 (1H, m), 1.76-1.65 (6H, m), 2.98-2.89 (3H, m), 3.18-3.15 (2H, m), 3.54 (1H, br s), 4.10 (1H, m), 4.15 (1H, d, J = 4.7 Hz), 6.83 (1H, d, J = 7.6 Hz), 6.96 (1H, dt, J = 0.9, 7.5 Hz), 7.24-7.12 (6H, m), 10.4 (1H, s), 11.1 (1H, br s) ppm.
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RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 8,6, 21,5, 23,5, 24,9, 30,4, 36,6, 48,7, 51,5, 53,2, 54,9, 109,4, 121,7, 123,2, 126,7, 126,7, 127,7, 127,8, 128,6, 128,7, 131,6, 132,1, 142,7, 180,8 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 8.6, 21.5, 23.5, 24.9, 30.4, 36.6, 48.7, 51.5, 53.2, 54.9, 109.4, 121.7, 123.2, 126.7, 126.7, 127.7, 127.8, 128.6, 128.7, 131.6, 132.1, 142.7, 180.8 ppm.
Análisis elemental de la fórmula C_{23}H_{29}ClN_{2}O (384,95):Elemental analysis of the formula C 23 H 29 ClN 2 O (384.95):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 4-(4-fluoro-fenil)-1,2,3,6-tetrahidropiridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 2.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 4- (4-fluoro-phenyl) -1,2,3,6-tetrahydropyridine. The product was isolated from the reaction mixture by application of the processing procedure 2.
P.f.: 108ºC a 111ºC.Mp .: 108 ° C to 111 ° C.
IR (KBr): 3426, 1705 (C=O) cm^{-1}.IR (KBr): 3426, 1705 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,51 (3H, t, J=7,4 Hz), 0,78-0,88 (1H, m), 0,94-1,02 (1H, m), 1,64-1,83 (6H, m), 2,86-3,80 (6H, m), 2,98 (2H, t, J=8,1 Hz), 6,12 (1H, s), 6,87 (1H, d, J=7,7 Hz), 7,00 (1H, dt, J=0,9, 7,5 Hz), 7,15-7,23 (4H, m), 7,52 (2H, m), 10,45 (1H, s), 10,9 (1H, br s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.78-0.88 (1H, m), 0.94-1.02 (1H, m), 1.64-1.83 (6H, m), 2.86-3.80 (6H, m), 2.98 (2H, t, J = 8.1 Hz), 6.12 (1H, s), 6.87 (1H, d, J = 7.7 Hz), 7.00 (1H, dt, J = 0.9, 7.5 Hz), 7.15-7.23 (4H, m), 7.52 (2H, m), 10.45 (1H, s), 10.9 (1H, br s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 400 MHz): 8,6, 21,5, 23,6, 23,8, 30,4, 36,6, 48,0, 49,4, 53,2, 54,6, 109,3, 115,5 (d, J=21,4 Hz), 116,5, 121,7, 123,2, 127,0 (d, J=8,0 Hz), 127,8, 132,1, 133,3, 134,9 (d, J=3,1 Hz), 142,7, 162,0 (d, J=244,9 Hz), 180,8 ppm.NMR - 13 C (DMSO-d6, TMS, 400 MHz): 8.6, 21.5, 23.6, 23.8, 30.4, 36.6, 48.0, 49.4, 53.2, 54.6, 109.3, 115.5 (d, J = 21.4 Hz), 116.5, 121.7, 123.2, 127.0 (d, J = 8.0 Hz), 127.8, 132.1, 133.3, 134.9 (d, J = 3.1 Hz), 142.7, 162.0 (d, J = 244.9 Hz), 180.8 ppm.
Análisis elemental de la fórmula C_{25}H_{30}ClFN_{2}O (428,98):Elemental analysis of the formula C 25 H 30 ClFN 2 O (428.98):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 4-(4-clorofenil)-1,2,3,6-tetrahidropiridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 1.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine. The product was isolated from the reaction mixture by application of the processing procedure 1.
P.f.: 142ºC a 145ºC (hexano-acetato de etilo).Mp .: 142 ° C to 145 ° C (hexane-ethyl acetate).
IR (KBr): 3181, 1715, 1701 (C=O) cm^{-1}.IR (KBr): 3181, 1715, 1701 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 400 MHz): 0,61 (3H, t, J=7,4 Hz), 0,96-0,84 (1H, m), 1,17-1,04 (1H, m), 1,46-1,35 (2H, m), 1,95-1,73 (4H, m), 2,29 (2H, t, J=7,8 Hz), 2,45 (2H, m), 2,58 (2H, t, J=5,6 Hz), 3,03 (2H, q, J=2,8 Hz), 5,99 (1H, t, J=1,8 Hz), 6,88 (1H, d, J=7,7 Hz), 7,02 (1H, dt, J=1,0, 7,5 Hz), 7,10 (1H, d, J=6,4 Hz), 7,17 (1H, dt, J=1,4, 7,6 Hz), 7,27-7,21 (4H, m), 8,63 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 400 MHz): 0.61 (3H, t, J = 7.4 Hz), 0.96-0.84 (1H, m), 1.17-1.04 (1H, m), 1.46-1.35 (2H, m), 1.95-1.73 (4H, m), 2.29 (2H, t, J = 7.8 Hz), 2.45 (2H, m), 2.58 (2H, t, J = 5.6 Hz), 3.03 (2H, q, J = 2.8 Hz), 5.99 (1H, t, J = 1.8 Hz), 6.88 (1H, d, J = 7.7 Hz), 7.02 (1H, dt, J = 1.0, 7.5 Hz), 7.10 (1H, d, J = 6.4 Hz), 7.17 (1H, dt, J = 1.4, 7.6 Hz), 7.27-7.21 (4H, m), 8.63 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 101 MHz): 8,6, 22,1, 26,9, 27,4, 30,5, 37,2, 49,9, 52,8, 53,3, 57,5, 109,2, 121,6, 123,1, 123,1, 126,4, 127,6, 128,4, 131,5, 132,4, 132,9, 139,1, 142,7, 181,0 ppm.NMR - 13 C (DMSO-d6, TMS, 101 MHz): 8.6, 22.1, 26.9, 27.4, 30.5, 37.2, 49.9, 52.8, 53.3, 57.5, 109.2, 121.6, 123.1, 123.1, 126.4, 127.6, 128.4, 131.5, 132.4, 132.9, 139.1, 142.7, 181.0 ppm.
Análisis elemental de la fórmula C_{25}H_{29}ClN_{2}O (408,98):Elemental analysis of the formula C 25 H 29 ClN 2 O (408.98):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(4-clorobutil)-3-etil-1,3-dihidro-2H-indol-2-ona y 4-(3-clorofenil)-1,2,3,6-tetrahidropiridina. Se aisló el producto a partir de la mezcla de reacción mediante la aplicación del procedimiento de procesado 2.The title compound was prepared according to "D" procedure, starting from 3- (4-Chlorobutyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 4- (3-chlorophenyl) -1,2,3,6-tetrahydropyridine. The product was isolated from the reaction mixture by application of the processing procedure 2.
P.f.: 82ºC a 85ºC.Mp .: 82 ° C to 85 ° C.
IR (KBr): 3421, 3168, 1706 (C=O) cm^{-1}.IR (KBr): 3421, 3168, 1706 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 200 MHz): 0,51 (3H, t, J=7,3 Hz), 1,03-0,83 (2H, m), 1,96-1,60 (6H, m), 4,0-2,76 (8H, m), 6,25 (1H, s), 6,87 (1H, d, J=7,6 Hz), 7,00 (1H, t, J=7,3 Hz), 7,52-7,15 (6H, m), 10,47 (1H, s), 10,92 (1H, br s) ppm.NMR - 1 H (DMSO-d6, TMS, 200 MHz): 0.51 (3H, t, J = 7.3 Hz), 1.03-0.83 (2H, m), 1.96-1.60 (6H, m), 4.0-2.76 (8H, m), 6.25 (1H, s), 6.87 (1H, d, J = 7.6 Hz), 7.00 (1H, t, J = 7.3 Hz), 7.52-7.15 (6H, m), 10.47 (1H, s), 10.92 (1H, br s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 50,3 MHz): 8,62, 21,5, 23,6, 30,4, 36,7, 47,9, 49,4, 53,2, 54,6, 109,4, 118,2, 121,7, 123,2, 123,7, 124,9, 127,8, 127,9, 130,6, 132,2, 133,1, 133,7, 140,7, 142,7, 180,8 ppm.NMR - 13 C (DMSO-d6, TMS, 50.3 MHz): 8.62, 21.5, 23.6, 30.4, 36.7, 47.9, 49.4, 53.2, 54.6, 109.4, 118.2, 121.7, 123.2, 123.7, 124.9, 127.8, 127.9, 130.6, 132.2, 133.1, 133.7, 140.7, 142.7, 180.8 ppm.
Análisis elemental de la fórmula C_{25}H_{30}Cl_{2}N_{2}O (445,44):Elemental analysis of the formula C 25 H 30 Cl 2 N 2 O (445.44):
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Se preparó el compuesto del título según el procedimiento "D", partiendo de 3-(6-bromohexil)-3-etil-1,3-dihidro-2H-indol-2-ona y 2-cloro-6,7-dihidro-4H-tieno[3,2-c]piridina. Se aisló el producto según el procedimiento de tratamiento 2 a partir de la mezcla de reacción.The title compound was prepared according to "D" procedure, starting from 3- (6-Bromohexyl) -3-ethyl-1,3-dihydro-2H-indole-2-one Y 2-Chloro-6,7-dihydro-4H-thieno [3,2-c] pyridine. The product was isolated according to treatment procedure 2 a from the reaction mixture.
Punto de fusión: 82ºC a 85ºC.Melting point: 82 ° C to 85 ° C.
IR (KBr): 3169, 2560, 1708 (C=O), 752 (C-Cl) cm^{-1}.IR (KBr): 3169, 2560, 1708 (C = O), 752 (C-Cl) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 200 MHz): 0,49 (3H, J=7,3 Hz), 0,95-0,78 (2H, m), 1,24-1,15 (4H, m), 1,74-1,65 (6H, m), 3,05 (4H, t, J=7,3 Hz), 3,38 (2H, m), 4,14 (2H, m), 6,85 (1H, d, J=7,7 Hz), 6,94 (1H, s), 7,01 (1H, dt, J=1,1, 8,4 Hz), 7,21-7,12 (3H, m), 10,42 (1H, s), 11,3 (1H, sz) ppm.NMR - 1 H (DMSO-d6, TMS, 200 MHz): 0.49 (3H, J = 7.3 Hz), 0.95-0.78 (2H, m), 1.24-1.15 (4H, m), 1.74-1.65 (6H, m), 3.05 (4H, t, J = 7.3 Hz), 3.38 (2H, m), 4.14 (2H, m), 6.85 (1H, d, J = 7.7 Hz), 6.94 (1H, s), 7.01 (1H, dt, J = 1.1, 8.4 Hz), 7.21-7.12 (3H, m), 10.42 (1H, s), 11.3 (1H, sz) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 50,3 MHz): 8,4, 1,7, 23,3, 23,7, 25,9, 28,7, 30,3, 36,9, 48,6, 49,3, 53,1, 54,7, 109,1, 121,4, 122,9, 124,8, 127,0, 127,5, 128,1, 131,0, 132,2, 142,5, 180,8 ppm.NMR - 13 C (DMSO-d6, TMS, 50.3 MHz): 8.4, 1.7, 23.3, 23.7, 25.9, 28.7, 30.3, 36.9, 48.6, 49.3, 53.1, 54.7, 109.1, 121.4, 122.9, 124.8, 127.0, 127.5, 128.1, 131.0, 132.2, 142.5, 180.8 ppm.
Análisis elemental de la fórmula C_{23}H_{30}Cl_{2}N_{2}OS (453,48):Elemental analysis of the formula C 23 H 30 Cl 2 N 2 OS (453.48):
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Se preparó el compuesto del título según el procedimiento D, partiendo de 3-(4-clorobutil)-3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 4-(3-clorofenil)-1,2,3,6-tetrahidro-piridina. Se aisló el producto mediante el procedimiento de procesado 1.The title compound was prepared according to procedure D, starting from 3- (4-Chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one Y 4- (3-chlorophenyl) -1,2,3,6-tetrahydro-pyridine. The product was isolated by the process of processing 1.
Punto de fusión: 112ºC a 114ºC.Melting point: 112 ° C to 114 ° C.
IR (KBr): 3161, 1706 (C=O), 817 cm^{-1}.IR (KBr): 3161, 1706 (C = O), 817 cm -1.
RMN-^{1}H
(DMSO-d_{6}, TMS, 500 MHz): 0,50 (3H, t, J=7,4
Hz), 0,81-0,77 (1H, m), 0,98-0,94
(1H, m), 1,38-1,28 (2H, m),
1,80-1,68 (4H, m), 2,23 (2H, t, J=7,2 Hz), 2,38 (2,
d, J=1,6 Hz), 2,52-2,48 (2H, m), 2,96 (2H, t, J=2,6
Hz), 6,19 (1H, kv, J=1,8 Hz), 6,80 (1H, dd, J=4,5, 8,2 Hz), 6,98
(1H, ddd, J=2,7, 8,5, 9,8 Hz), 7,16 (1H, dd, J=2,7, 8,5 Hz),
7,28
(1H, td, J=1,8, 7,4 Hz), 7,33 (1H, t, J=7,7 Hz), 7,37
(1H, td, J=1,6, 7,9 Hz), 7,42 (1H, t, J=1,6 Hz), 10,35 (1H, s)
ppm.1 H NMR (DMSO-d 6, TMS, 500 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.81-0.77 (1H, m), 0.98-0.94 (1H, m), 1.38-1.28 (2H, m), 1.80-1.68 (4H, m), 2.23 (2H, t, J = 7 , 2 Hz), 2.38 (2, d, J = 1.6 Hz), 2.52-2.48 (2H, m), 2.96 (2H, t, J = 2.6 Hz), 6.19 (1H, kv, J = 1.8 Hz), 6.80 (1H, dd, J = 4.5, 8.2 Hz), 6.98 (1H, ddd, J = 2.7, 8.5, 9.8 Hz), 7.16 (1H, dd, J = 2.7, 8.5 Hz), 7.28
(1H, td, J = 1.8, 7.4 Hz), 7.33 (1H, t, J = 7.7 Hz), 7.37 (1H, td, J = 1.6, 7.9 Hz), 7.42 (1H, t, J = 1.6 Hz), 10.35 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 125,6 MHz): 8,5, 22,0, 26,8, 27,3, 30,4, 37,0, 49,8, 52,8, 54,1, 57,4, 109,8 (d, J=7,8 Hz), 111,2 (d, J=24,4 Hz), 113,8 (d, J=23,4 Hz), 123,3, 123,9, 124,5, 126,8, 130,3, 132,9, 133,5, 134,5 (d, J=7,8 Hz), 138,8, 142,5, 158,3 (d, J=236,3 Hz), 180,9 ppm.NMR - 13 C (DMSO-d 6, TMS, 125.6 MHz): 8.5, 22.0, 26.8, 27.3, 30.4, 37.0, 49.8, 52.8, 54.1, 57.4, 109.8 (d, J = 7.8 Hz), 111.2 (d, J = 24.4 Hz), 113.8 (d, J = 23.4 Hz), 123.3, 123.9, 124.5, 126.8, 130.3, 132.9, 133.5, 134.5 (d, J = 7.8 Hz), 138.8, 142.5, 158.3 (d, J = 236.3 Hz), 180.9 ppm.
Análisis elemental de la fórmula C_{25}H_{28}ClFN_{2}O (426,97)Elemental analysis of the formula C 25 H 28 ClFN 2 O (426.97)
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Se preparó el compuesto del título según el procedimiento D, partiendo de 3-(4-clorobutil)-3-etil-5-fluoro-1,3-dihidro-2H-indol-2-ona y 4-(4-clorofenil)-1,2,3,6-tetrahidro-piridina. Se aisló el producto utilizando el procedimiento de procesado 1.The title compound was prepared according to procedure D, starting from 3- (4-Chlorobutyl) -3-ethyl-5-fluoro-1,3-dihydro-2H-indole-2-one Y 4- (4-chlorophenyl) -1,2,3,6-tetrahydro-pyridine. The product was isolated using the processing procedure one.
Punto de fusión: 146ºC a 148ºC.Melting point: 146 ° C to 148 ° C.
IR (KBr): 3289, 1717 (C=O), 1689, 818 cm^{-1}.IR (KBr): 3289, 1717 (C = O), 1689, 818 cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 500 MHz): 0,50 (3H, t, J=7,4 Hz), 0,83-0,77 (1H, m), 0,99-0,93 (1H, m), 1,40-1,31 (2H, m), 1,51-1,68 (4H, m), 2,28 (2H, m, sz), 2,40 (2H, sz), 2,56 (2H, sz), 3,02 (2H, sz), 6,14 (1H, kv, J=1,9 Hz), 6,81 (1H, dd, J=4,5, 8,4 Hz), 6,98 (1H, ddd, J=2,7, 8,4, 9,7 Hz), 7,16 (1H, dd, J=2,8, 8,4 Hz), 7,37 (2H, d, J=8,8 Hz), 7,43 (2H, d, J=8,8 Hz), 10,38 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 500 MHz): 0.50 (3H, t, J = 7.4 Hz), 0.83-0.77 (1H, m), 0.99-0.93 (1H, m), 1.40-1.31 (2H, m), 1.51-1.68 (4H, m), 2.28 (2H, m, sz), 2.40 (2H, sz), 2.56 (2H, sz), 3.02 (2H, sz), 6.14 (1H, kv, J = 1.9 Hz), 6.81 (1H, dd, J = 4.5, 8.4 Hz), 6.98 (1H, ddd, J = 2.7, 8.4, 9.7 Hz), 7.16 (1H, dd, J = 2.8, 8.4 Hz), 7.37 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 10.38 (1H, s) ppm.
RMN-^{13}C (DMSO-d_{6}, TMS, 125,6 MHz): 8,5, 22,0, 26,5, 27,1, 30,4, 37,0, 49,7, 52,5, 54,1 (d, J=2,0 Hz), 57,2, 109,8 (d, J=7,8 Hz), 111,1 (d, J=23,9 Hz), 113,8 (d, J=23,0 Hz), 122,6, 126,4, 128,4, 131,6, 132,9, 134,5 (d, J=7,8 Hz), 138,8 (d, J=1,5 Hz), 138,9, 158,3 (d, J=236,3 Hz), 180,8 ppm.NMR - 13 C (DMSO-d6, TMS, 125.6 MHz): 8.5, 22.0, 26.5, 27.1, 30.4, 37.0, 49.7, 52.5, 54.1 (d, J = 2.0 Hz), 57.2, 109.8 (d, J = 7.8 Hz), 111.1 (d, J = 23.9 Hz), 113.8 (d, J = 23.0 Hz), 122.6, 126.4, 128.4, 131.6, 132.9, 134.5 (d, J = 7.8 Hz), 138.8 (d, J = 1.5 Hz), 138.9, 158.3 (d, J = 236.3 Hz), 180.8 ppm.
Análisis elemental de la fórmula C_{25}H_{28}ClFN_{2}O (426,97):Elemental analysis of the formula C 25 H 28 ClFN 2 O (426.97):
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Se preparó el compuesto del título según el procedimiento D, utilizando 3-(4-clorobutil)-3-etil-6-fluoro-1,3-dihidro-2H-indol-2-ona y 4-(3-clorofenil)-1,2,3,6-tetrahidro-piridina como compuesto de partida. Se aisló el producto según el procedimiento de procesado 2.The title compound was prepared according to procedure D, using 3- (4-Chlorobutyl) -3-ethyl-6-fluoro-1,3-dihydro-2H-indole-2-one Y 4- (3-chlorophenyl) -1,2,3,6-tetrahydro-pyridine as starting compound. The product was isolated according to processing procedure 2.
Punto de fusión: 101ºC a 104ºC.Melting point: 101 ° C to 104 ° C.
IR (KBr): 3158, 2877, 1715 (C=O) cm^{-1}.IR (KBr): 3158, 2877, 1715 (C = O) cm -1.
RMN-^{1}H (DMSO-d_{6}, TMS, 500 MHz): 0,51 (3H, t, J=7,4 Hz), 0,97-0,80 (2H, m), 1,81-1,63 (6H, m), 3,73-2,51 (8H, m), 6,20 (1H, s), 6,82-6,67 (2H, m), 7,50-7,20 (5H, m), 8,8 (1H, sz), 10,6 (1H, s) ppm.NMR - 1 H (DMSO-d6, TMS, 500 MHz): 0.51 (3H, t, J = 7.4 Hz), 0.97-0.80 (2H, m), 1.81-1.63 (6H, m), 3.73-2.51 (8H, m), 6.20 (1H, s), 6.82-6.67 (2H, m), 7.50-7.20 (5H, m), 8.8 (1H, sz), 10.6 (1H, s) ppm.
Análisis elemental de la fórmula C_{25}H_{29}Cl_{2}FN_{2}O (463,43):Elemental analysis of the formula C 25 H 29 Cl 2 FN 2 O (463.43):
Claims (14)
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